At the end of Hewson's superb Sacred Cut (2005), Roman cops Nic Costa and Gianni Peroni, along with their maverick boss, Leo Falcone, were all in jeopardy, having both outfoxed and offended the Eternal City's leading powerbrokers.

The game begins with the fact that Sam Fisher, Third Echelon leaves, despite threats from his superiors. And during the investigation into the death of his daughter, Sarah Fisher (who died in an accident caused by drunk drivers during the Double Agent), Sam learns that his daughter's death was not accidental, and now he and Victor Costa, the former "sea lion" and longtime friend, will lead the hunt for Andrew Kobina, the arms dealer, who presumed to Sam, killed his daughter.