The history of smallpox in Africa during colonial rule is a relatively neglected subject. This is not because of ignorance or obscurity but in some ways just the opposite: it is thought that there is little more to be learned about it. To be sure, vaccination campaigns during colonial rule were one of the earliest and most extensive public health programmes that Europeans bragged about as evidence of the advantages of colonial rule: “an appreciable agent of propaganda”, is how one French colonial medical officer described smallpox vaccination.1 The mass campaigns used mostly African personnel and produced effective results. Moreover, at the end of colonial rule and beginning of independence, smallpox gained worldwide attention when the World Health Organization (WHO) launched its smallpox eradication programme. Now the colonial measures were criticized as not going far enough, and data on epidemics and prevalence were the subject of much study as measures were taken which successfully eliminated the scourge in the 1960s and early 1970s. Since then, the magisterial volume by the principal leaders of that effort, Frank Fenner, and his co-authors, has been taken as more or less the last word on the subject, not just in Africa but worldwide. This is appropriate, to a large extent. The sections on Africa in the volume, and another by one of their collaborators, Donald Hopkins, are thoroughly documented, based on a large amount of evidence, and certainly the starting point for anyone wishing to revisit the subject.2 But these authors have a particular point of view, given their involvement in the campaign, which minimizes earlier efforts. Hence the chapters on colonial rule focus primarily on the epidemiology of smallpox, with little about attempts to prevent or respond to epidemics when they occurred.3 This study focuses on the efforts at smallpox control and prevention from the 1920s to the end of colonial rule in West, Central and East Africa. These were by far the earliest and for a long time the largest efforts at introducing Western medicine to Africa. To the extent they succeeded, even though not completely, they were a model for further public health efforts, including the WHO eradication campaign. To the extent that they failed, the campaigns offer a lesson for contemporary efforts to reduce, let alone eradicate, diseases in tropical settings. In addition to showing the extent of smallpox vaccination in colonial Africa, this study also examines assessments at the time about the effectiveness of such attempts at control and prevention and the wider context in which they were undertaken. It supports the most important lesson drawn by those involved in the WHO eradication campaign: that only a worldwide and comprehensive effort could succeed in eliminating the periodic epidemics that plagued places such as Africa. Without sufficient vaccination protection, even if a particular colony had no new cases for a number of years, isolated cases or smallpox brought in by travellers from outside eventually reached small pockets of those unvaccinated, with devastating results. That did not mean authorities before 1958 did not try, and those efforts show significant success in containing and eliminating outbreaks when they occurred. After the eradication of smallpox, there were great hopes of eliminating other contagious diseases.4 This not only failed to occur but new diseases, such as HIV/AIDS, have emerged which means we are back in a situation of trying to control and eliminate diseases, much as colonial authorities attempted in the first half of the twentieth century in Africa. A re-examination of their efforts is therefore warranted.