At the Villa Auditore, Ezio talked to his uncle in order to travel to Rome.
- Mario: Roma beckons, Ezio. Let me know when you are ready to depart.
He and Mario traveled to Rome, with the latter leaving his nephew at a dock just under the Castel Sant'Angelo. The Assassin then made his way up the side of – and through – the complex, until he reached a watchtower. As the guards were alerted to his presence, Ezio leapt onto a horse in the great wall under his position.
- Guard 1: Assassino! Assassino! (Assassin! Assassin!)
- Guard 2: Close the gates! Stop the intruder!
Despite some minor resistance, Ezio crossed the Passetto di Borgo by horse and, then, by foot, while fleeing and killing the soldiers. He successfully managed to enter the Sistine Chapel, where he found the Grand Master of the Italian Templars and Pope proclaiming the Nicene Creed to the cardinals during Mass.
- Rodrigo: Credo in unum Deum, Patrem omnipoténtem, factórem cæli et terræ, visibílium ómnium et invisibílium. Et in unum Dóminum, Iesum Christum, Fílium Dei unigénitum, et ex Patre natum ante ómnia sǽcula. Deum de Deo, lumen de lúmine, Deum verum de Deo vero, génitum, non factum, consubstantiálem Patri: per quem ómnia facta sunt. Qui propter nos hómines et propter nostram salútem descéndit de cælis. Et incarnátus est de Spíritu Sancto ex María Vírgine, et homo factus est. Crucifíxus étiam pro nobis sub Pontius Pilate; passus et sepúltus est, et resurréxit tértia die, secúndum Scriptúras, et ascéndit in cælum, sedet ad déxteram Patris. Et íterum ventúrus est cum glória, iudicáre vivos et mórtuos, cuius regni non erit finis. Et in Spíritum Sanctum, Dóminum et vivificántem: qui ex Patre Filióque procédit. Qui cum Patre et Fílio simul adorátur et conglorificátur: qui locútus est per prophétas. Et unam, sanctam, cathólicam et apostólicam Ecclésiam. Confíteor unum baptísma in remissiónem peccatórum. Et exspécto resurrectiónem mortuórum, et vitam ventúri sǽculi. Amen.
Ezio entered the large room through some scaffoldings and attempted to air assassinate Rodrigo with his Hidden Blade.
- Ezio: I thought... I thought I was beyond this. But I'm not. I've waited too long... lost too much... Requiescat in pace (Rest in peace), you bastard.
- Rodrigo: I don't think so!
Rodrigo picked up his Staff to knock him away with it and used its power to drain the vitality of everyone present, causing all but Ezio to collapse.
- Rodrigo: How is it you resist?
He looked to the glowing pouch attached to Ezio's waist.
- Rodrigo: I see... Kind of you to bring me the Apple. Now give it here!
- Ezio: Vai a farti fottere. (Go fuck yourself.)
- Rodrigo: Ahh, always the fighter. Just like your father. Well—rejoice, my child—for you will see him again SOON! You WILL give it to me!
- Ezio: As you wish.
Ezio used the Apple to create an illusion of himself splitting into five duplicates.
- Rodrigo: Fascinating! An impressive power, this. But if you think it's going to save you, you've another thing coming!
He began fighting Ezio and the illusions, using the Staff as a spear, uncertain as to which of them was the real one.
- Rodrigo: How long do you think you can keep this up?
A clever trick! But useless!
You cannot stop me!
You are right to fear me!
I'll cut you down, Assassin!
Ezio won the fight, putting the Pope on his knees.
- Rodrigo: No! You will not take this from me...
- Ezio: It's finished, Rodrigo. Lay down your arms and I'll make sure the end comes swiftly.
- Rodrigo: Really, Ezio? And would you give up so easily were it the other way around?
Rodrigo smashed the Staff into the ground, causing Ezio to fall.
- Rodrigo: Why don't we find out!
He then utilized the artifact to become invisible. In response, Ezio pulled out the Apple in an attempt to defend himself, but Rodrigo stepped on Ezio's arm, causing him to scream and drop the Piece of Eden.
- Rodrigo: At last!
Rodrigo picked up the Apple and attached it to the top of the Staff.
- Rodrigo: And now to deal with you.
A glowing aura surrounded a vulnerable Ezio as Rodrigo suspended him into the air with the Staff and stabbed him in the gut with a dagger, before taking the Apple and disappearing below ground. Weak from blood loss, Ezio fell unconscious, but survived the wound due to the Armor of Altaïr. The Assassin then found two switches hidden in the walls of the room by using his Eagle Vision, opening a passageway on the floor of the altar. He went down the entrance and made his way through the corridors, sided by blue and futuristic lights, until he reached a grand room composed of unusual architecture and a smaller chamber on the ground.
- Ezio: What is this place...?
He dropped down into the antechamber of the Vault, where the Templar desperately tried to open its door.
- Rodrigo: Open, damn you! OPEN!
- Ezio: It's over, Rodrigo. No more tricks. No more ancient artifacts. No more weapons. Let us see what you are made of, old man.
- Rodrigo: Alright then, if that's how you want to play it.
Ezio and Rodrigo engaged in a fistfight.
- Ezio: What do you even want with the Vault, Rodrigo?
- Rodrigo: Don't you know what lies within? Or do you mean to tell me the great and powerful Assassins didn't figure it out?
- Ezio: Figure what out?
- Rodrigo: God! It's God that dwells within!
- Ezio: You expect me to believe that God lives beneath il Vaticano? (the Vatican?)
- Rodrigo: A more logical location than a kingdom on a cloud, don't you think? Surrounded by singing angels and cherubim. Makes for a lovely image—but the TRUTH is far more interesting.
- Ezio: Let's say I was to believe you—what do you think he'll do when you open that door?
- Rodrigo: I don't care. It's not approval I'm after. Just power.
- Ezio: And you think he'll give it up?
- Rodrigo: Whatever lies beyond that wall won't be able to resist the staff and apple. They were MADE for felling Gods.
- Ezio: God is meant to be all knowing. All powerful. You think a couple of ancient relics can harm him?
- Rodrigo: You know nothing, boy. You take your image of the creators from an ancient book—a book, mind you, written by MEN.
- Ezio: You are the Pope! And yet you dismiss the central text of your Faith?
- Rodrigo: Are you so naïve? I became Pope because it gave me ACCESS. It gave me POWER. Do you think I believe a single god-damned word of that ridiculous book? It's all lies and superstition. Just like every OTHER religious tract written over the past ten thousand years.
Gaining the upper hand, Ezio grabbed Rodrigo by the throat and choked him, before throwing him to the ground.
- Rodrigo: You can't! You can't! It's MY destiny! MINE! I am the prophet!
- Ezio: You never were...
- Rodrigo: Get it over with then.
Ezio stood up and stepped back, letting him go.
- Ezio: No. Killing you won't bring my family back... I'm done. Nulla è reale, tutto è lecito. Requiescat in pace. (Nothing is true, everything is permitted. Rest in peace.)
The Staff and Apple at the center of the chamber emmited a golden light, embroiled in various strange glyphs. Ezio carefully approached them and touched the shaft of the Staff. The relics recognized his DNA, generating light beems which pointed to the door and opened it, granting him access to the Vault. Leaving a stunned Rodrigo behind, Ezio entered it. As he did so, an hologram of Minerva, one of the members of the First Civilization, appeared and spoke to him.
- Minerva: Greetings prophet. It is good you have come. Let us see it. To give thanks.
He held out the Apple of Eden for Minerva to see, and she touched it in response.
- Minerva: We must speak.
- Ezio: Who are you?
- Minerva: Many names. When I died, it was Minerva. Before that Merva and Mera. And on and on. The others, too: Juno, who was before called Uni. Jupiter, who was before called Tinia...
Amazed with his surroundings and the figure of the Isu, Ezio greeted Minerva as he saw fit.
- Ezio: You are... gods.
- Minerva: No. Not gods. We simply came... before. Even when we walked the world, your kind struggled to understand our existence. We were more... advanced in time. Your minds were not yet ready. Still... not. Maybe never. No matter. You may not comprehend us. But you will comprehend our warning. You must.
- Ezio: None of what you are saying makes sense...
- Minerva: Our words are not meant for you.
Confused, he looked around the room as the hologram looked away from him, seemingly at someone else.
- Ezio: What are you talking about? There's no one else here!
With her time running short, she reprimanded Ezio.
- Minerva: Enough! I do not wish to speak with you but through you. You are the prophet. You've played your part. You anchor him, but please be silent! That we may commune.
He remained silent as Minerva's figure disappeared and conveyed the message.
- Minerva: Listen: When we were still flesh and our home still whole, your kind betrayed us. We who made you. We, who gave you life! We were strong. But you were many. And both of us craved war. So busy were we with earthly concerns, we failed to notice the heavens. And by the time we did... The world burned until naught remained but ash. It should have ended then and there. But we built you in our own image. We built you to survive. And so we did. Few were our numbers. Your kind and mine. It took sacrifice. Strength. Compassion. But we rebuilt. And as life returned to the world... We endeavored to ensure this tragedy would not be repeated. But now we are dying... And time will work against us. Truth turned into myth and legend. What we built, misunderstood. Let my words preserve the message and make a record of our loss. But let my words also bring hope. You must find the other temples. Built by those who knew to turn away from war. They worked to protect us—to save us from the fire. If you can find them... If their work can be saved... so too might this world. Be quick! For time grows short. And guard against the cross—for there are many who will stand in your way.
Minerva appeared before him once again, but continued to stare beyond his position.
- Minerva: It is done. The message is delivered. We are gone now from this world. All of us. We can do no more. The rest is up to you, Desmond.
- Ezio: What? Who is Desmond? I don't understand... Please, wait! I have so many questions!
The hologram faded, leaving Ezio alone in the room.
Rodrigo Borgia was spared and Ezio spoke to Minerva in the Vatican Vault and learned of her people, along with a great tragedy that would befall mankind being revealed to him. In response to the message, Ezio was left with many questions unanswered as the hologram disappeared.
- "In bocca al lupo" means "Into the mouth of a wolf," which is an Italian saying for good luck, being the equivalent of "break a leg." The traditional response is "crepi il lupo", or "may the wolf die"; Crepi il Lupo is a mission in Assassin's Creed: Brotherhood.
- Ezio and Antonio de Magianis exchange this blessing earlier in the game, in the memory Everything Must Go.
- In the Italian version of Assassin's Creed II, the name of the memory refers to another saying involving wolves. It is called Nella tana del lupo, which translates to In the Wolf's Den (comparable to the English into the lion's den).
- When Ezio entered the Sistine Chapel, Rodrigo was proclaiming the Nicene Creed in Latin to the congregation. Ironically, he later stated that he did not believe the concept of the Nicene Creed, which confesses the wholeness of the Roman Catholic doctrine.
- When Assassin's Creed: Brotherhood picked up from where Assassin's Creed II left off, with Ezio just having talked with Minerva, Ezio had a more ornate cape, rather than a plain brown one seen in Assassin's Creed II, and was wearing the armor of Altaïr Ibn-La'Ahad. He also had his weapons by his side, despite the fact that he had never picked them up after fighting Rodrigo.
- Even though Ezio had the Apple taken from him, he still had the pouch which held it by his side while battling Rodrigo.