Familial clustering and ethnic differences suggest that visceral leishmaniasis caused by Leishmania donovani is under genetic control. A recent genome scan provided evidence for a major susceptibility gene on Chromosome 22q12 in the Aringa ethnic group in Sudan. We now report a genome- wide scan using 69 families with 173 affected relatives from two villages occupied by the related Masalit ethnic group. A primary ten-centimorgan scan followed by refined mapping provided evidence for major loci at 1p22 ( LOD score 5.65; nominal p = 1.72 x 10(-7); empirical p = 1 x 10(-5); lambda(S) 5.1) and 6q27 ( LOD score 3.74; nominal p = 1.68 x 10(-5); empirical p < 1 x 10(-4); lambda(S) = 2.3) that were Y chromosome lineage and village- specific. Neither village supported a visceral leishmaniasis susceptibility gene on 22q12. The results suggest strong lineage- specific genes due to founder effect and consanguinity in these recently immigrant populations. These chance events in ethnically uniform African populations provide a powerful resource in the search for genes and mechanisms that regulate this complex disease.