This article explores two simultaneous epidemics that, despite similar pathologies, prompted significantly varying responses from public health actors in 1901 Cape Town: the bubonic plague and smallpox. The Cape Colony responded to the plague with racialized quarantining, forcibly removing all black Africans from certain poor neighborhoods and transferring them to a camp on the outskirts of the city. It was the most significant segregationist act in Cape Town’s history to date and foreshadowed the actions of governments in postunification and apartheid South Africa. Conversely, smallpox, though highly contagious and deadly, did not prompt similar aggression. Drawing from archival material, I argue that this differential treatment was the result of a global medical concern for the spread of plague to Europe that imposed external demands upon any region affected by plague that were nonexistent for smallpox. These demands aligned with local ideologies that equated state control with racial discipline to produce the first urban township in South Africa. This article addresses the global processes at work within seemingly localized epidemics and contributes to existing scholarship by exploring the role of medical experts and scientific knowledge in the framing of early pandemic threats.