Cholera outbreaks have occurred in Burundi, Rwanda, Democratic Republic of Congo, Tanzania, Uganda, and Kenya almost every year since 1977-1978, when the disease emerged in these countries. We used a multiscale, geographic information system-based approach to assess the link between cholera outbreaks, climate, and environmental variables. We performed time-series analyses and field investigations in the main affected areas. Results showed that cholera greatly increased during El Niño warm events (abnormally warm El Niños) but decreased or remained stable between these events. Most epidemics occurred in a few hotspots in lakeside areas, where the weekly incidence of cholera varied by season, rainfall, fluctuations of plankton, and fishing activities. During lull periods, persistence of cholera was explained by outbreak dynamics, which suggested a metapopulation pattern, and by endemic foci around the lakes. These links between cholera outbreaks, climate, and lake environments need additional, multidisciplinary study.