In histories of smallpox and vaccination, little attention has been paid to their progress in the southern latitudes. In this paper, I focus on the appearance of smallpox around Sydney Cove in 1789 and the introduction of cowpox (vaccine) to New South Wales in 1804. I demonstrate the connections, historical and virological, between the two events and examine the role of variolation in the spread of smallpox and in anticipating vaccination. I argue that imported "variolous matter," perhaps obtained in Cape Town, may have been the source of infection in the catastrophic epidemic among the Aborigines in 1789. I likewise examine the means by which vaccine was brought to Australia in relation to comparable initiatives around the Indian Ocean. I assess the significance of the early history of vaccination in Australia in relation to subsequent developments and as a remarkable demonstration of the global reach of the new prophylactic.