Parasitic diseases, including human visceral leishmaniasis, are multifactorial. Factors that are expected to play an important role in the parasite-human interaction are exposure, parasite "virulence" and host resistance factors. In populations exposed to Leishmania donovani most subjects do not allow the parasites to establish themselves or remain asymptomatic. Some individuals, however, fail to control parasite expansion and dissemination and develop a visceral disease. We report here the results of a longitudinal survey whose aims were to identify risk factors underlying visceral leishmaniasis (VL) susceptibility during an outbreak that occurred in a Sudanese village between 1995 and 1999. Most of the 660 subjects (90%) living in the central district were exposed to Leishmania and 20.9% (n = 138), mostly teenagers, developed VL. VL cases increased markedly in adults late in the outbreak, suggesting some changes in adult resistance status or in Leishmania "virulence" during the epidemic. Age and ethnic origin of the patients were the most important critical risk factors to account for the distribution of the VL cases that were recorded during the whole epidemic. This and the high frequency of VL in certain families suggest that host genetic factors played an important role in shaping the outbreak in this village. However, environmental factors (the presence of cows and neems in the households) that increase/decrease exposure to the parasite had significant effects on the distribution of VL cases in the village in the first phase of the outbreak.