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After the MacManus brothers, Conner and Murphy, and their father Noah assassinated Papa Joe Yakavetta, they fled to Ireland for eight years. One day, their uncle Sibeal arrives to inform them that a renowned Boston priest was murdered by a mysterious assassin who attempted to frame The Saints by using their same ritual assassination style. In response, the brothers dig up their old gear and weapons, and depart back to Boston.
En route aboard a container ship, they meet a Mexican underground fighter named Romeo, who recognizes them as The Saints. Romeo convinces them to let him join them as their new partner. Hearing a radio broadcast regarding Papa Joe's son, Concezio Yakavetta, they deduce that he hired the hit-man who killed the priest in order to draw them out of hiding.
Meanwhile, Detectives Dolly, Duffy, and Greenly are at the scene of the priest's murder. They are greeted by Special Agent Eunice Bloom, the protege of Paul Smecker (who apparently died a few years ago), and investigator to the priest’s death. They deduce that it was not The Saints who murdered him, beginning an investigation to find the real assassin. They later find the assassin’s name is Ottilio Panza, who appears to be working for a mysterious old man named "The Roman".
Meanwhile, Conner, Murphy, and Romeo hit a warehouse that is being used by an Asian gang to process heroin for Yakavetta. After killing everyone at the warehouse, Connor and Murphy reunite with their old bartender friend, Doc. They learn that the assassin was an independent contractor and not a part of Yakavetta's crew, and that Yakavetta himself is hiding in the Prudential Tower. Later at the warehouse, now a crime scene, Bloom asserts that The Saints have returned.
