Smallpox is regarded as an ancient and lethal disease of humans, however very little is known about the prevalence and impact of smallpox before the advent of vaccination (c.1800). Here we use evidence from English burial records covering the period 1650-1799 to confirm a striking geography to smallpox patterns. Smallpox apparently circulated as a childhood disease in northern England and Sweden, even where population densities were low and settlement patterns dispersed. However, smallpox was a relatively rare epidemic disease in southern England outside the largest cities, despite its commercialised economy and the growing spatial interconnectedness of its settlements. We investigated a number of factors hypothesised to influence the regional circulation of smallpox, including exposure to naturally occurring orthopox viruses, settlement patterns, and deliberate preventative measures. We concluded that transmission was controlled in southern England by local practices of avoidance and mass inoculation that arose in the seventeenth and eighteenth centuries. Avoidance measures included isolation of victims in pest houses and private homes, as well as cancellation of markets and other public gatherings, and pre-dated the widespread use of inoculation. The historical pattern of smallpox in England supports phylogenetic evidence for a relatively recent origin of the variola strains that circulated in the twentieth century, and provides evidence for the efficacy of preventative strategies complementary to immunisation.