In sub-Saharan Africa, many nomadic pastoralists have begun to settle in permanent communities as a result of long-term water, food, and civil insecurity. Little is known about the epidemiology of cholera in these emerging semi-nomadic populations. We report the results of a case-control study conducted during a cholera outbreak among semi-nomadic pastoralists in the Karamoja sub-region of northeastern Uganda in 2010. Data from 99 cases and 99 controls were analysed. In multivariate analyses, risk factors identified were: residing in the same household as another cholera case [adjusted odds ratio (aOR) 6·67, 95% confidence interval (CI) 2·83–15·70], eating roadside food (aOR 2·91, 95% CI 1·24–6·81), not disposing of children's faeces in a latrine (aOR 15·76, 95% CI 1·54–161·25), not treating drinking water with chlorine (aOR 3·86, 95% CI 1·63–9·14), female gender (aOR 2·43, 95% CI 1·09–5·43), and childhood age (10–17 years) (aOR 7·14, 95% CI 1·97–25·83). This is the first epidemiological study of cholera reported from a setting of semi-nomadic pastoralism in sub-Saharan Africa. Public health interventions among semi-nomadic pastoralists should include a two-faceted approach to cholera prevention: intensive health education programmes to address behaviours inherited from insecure nomadic lifestyles, as well as improvements in water and sanitation infrastructure. The utilization of community-based village health teams provides an important method of implementing such activities.