Beginning in 302 CE, the four emperors of the Roman tetrarchy collectively issued a series of edicts that decreed severe penalties against the Empire’s Manichaean and Christian subjects. These decrees constituted the most widespread and systematic religious persecutions in imperial history. In this chapter, I explore these edicts and their consequences in the context of a global history of genocide. I argue that, while these persecutions may not satisfy modern juristic definitions of genocide, which tend to emphasize physical violence, they nonetheless suggest that the emperors aimed to eliminate alternative systems of knowledge, to remove particular religio-cultural populations from the civic collective, and to prevent these groups’ social reproduction. I suggest the tetrarchy’s edicts comprise something akin to a “cultural genocide” by the Roman government. I conclude with some brief reflections on the use of cultural genocide as an interpretive tool for understanding ancient acts of community violence.