The most lethal and terrifying pandemic of the nineteenth century was smallpox. Well known in Europe, Asia and the Americas, this disease sporadically appeared in the Australian colonies until the 1830s. From this time onwards, maritime quarantine largely averted outbreaks or epidemics amongst Australia’s Aboriginal peoples and burgeoning colonial populations. New immigrants were required to have either recovered from smallpox or to have undergone Jennerian vaccination prior to boarding ships for the colonies. However, by the 1840s there was a large and rapidly growing cohort of Australian-born children who were immunologically naïve to smallpox. Although vaccine matter had first been transported to the continent in 1804, supply remained erratic and distribution was neither compulsory nor efficacious. In the context of minimal government investment in the health of free settlers, fear of a smallpox outbreak became a growing political concern. By 1845 the Governor and Legislative Council of New South Wales agreed to help fund the Sydney Infirmary and Dispensary in the city’s centre, providing limited inpatient and outpatient services for the ‘humble classes’ of citizens. By 1847 funds had also been allocated to establish a Vaccine Institution – the first immunological facility on the continent. Its fortunes wavered over the following decades, but this small centre was able to provide limited supplies of vaccine when smallpox threatened the city’s residents in 1853, 1876 and 1881. Although New South Wales never legislated for compulsory vaccination, the Vaccine Institution also provided significant lymph supplies to facilitate voluntary vaccination programs across the continent and around the Pacific Ocean. This presentation outlines the colonial health environment, particularly the risks posed by smallpox to a largely unprepared populace. It also considers the risks and benefits of vaccination in nineteenth-century context. In particular, this paper explores both the politics and epidemiology of preventive medicine in an era before widespread acceptance of immunisation, and indeed before modern concepts of microbiology.