There has been a murder at the CERN laboratory involving the theft of a canister of antimatter, which if not recovered before 24 hours, will explode. The canister has been taken to Vatican City by the Illuminati, who left their name branded on the chest of a murdered CERN physicist.
Langdon, who identified the brand as authentically Illuminati, along with the dead physicist's daughter, Vittoria, go to Vatican City. The Pope has just died and the candidates for the papacy are missing. Langdon begins a search for the kidnapped cardinals expecting the antimatter to be with them. He is joined by a man named Ventresca who was close to the Pope and worked with the Vatican Swiss Guard.
Langdon pursues the Illuminati by following the path given to those who seek entry into the secret society. In Rome, he discovers all four cardinals murdered in ways that echo the elements earth, wind, water and fire, each branded with an ambigram corresponding to their element. During the pursuit, Vittoria is kidnapped and Langdon continues on in search of the Illuminati, now for her rescue as well.
Langdon finds Vittoria in St. Peter's Basilica, and upon saving her hears Ventresca screaming. Langdon finds that he has been branded by the Illuminati. Kohler, who first saw the murder at CERN and called Langdon, is believed to be in the secret society, and is shot and killed, but not before he gives Langdon a tape which he says needs to be shown to the public.
With little time to spare, the Camerlengo, Ventresca, claims that a revelation from God has shown him the location off the antimatter: in the catacombs. The time bomb is found and is taken into the sky where it explodes harmlessly after a heart stopping moment that could have ended Langdon's life. Ventresca is considered for the papacy because of his miraculous vision, but it is revealed that the Camerlengo poisoned the Pope under the guise of the name Janus (revealing Janus' real identity) for the Pope's breach of his chastity vows and his sympathy to the natural sciences. The Camerlengo burns himself alive publicly to deal with his guilt and shame. Langdon and Vittoria consummate their love and Langdon receives the Illuminati diamond to be returned to the Vatican through his final will.