Familial clustering of disease, racial differences in asymptomatic:disease ratios, and studies of mice all point to a genetic component for disease susceptibility in visceral leishmaniasis. Analysis of 87 multi-case pedigrees (824 individuals; 138 nuclear families) from a region of northeastern Brazil endemic for Leishmania chagasi demonstrates a high relative risk ratio (2S = 34) to further siblings of affected sibling pairs. Complex segregation analysis using POINTER and COMDS show that all single locus models, as well as polygenic and multifactorial models, provide a signficantly (P