Twenty-four families with one or multiple cases of localized cutaneous leishmaniasis (LCL) from an endemic region with the highest incidence of LCL in Venezuela were typed from HLA-ABC, DR, DQ antigens and complement factors. The parental HLA haplotypes segregated at random among healthy and affected siblings but in backcross families significantly higher frequencies of HLA-A28 (p = 0.0018), -Bw22 (p = 0.0122), or -DQw8 (p = 0.0364) were present in affected compared to healthy siblings. HLA-B15 showed a higher frequency (p = 0.0062) among the latter group. Haplotypes Bw22CF31 (p = 0.0076) and Bw22DRw11DQw7 (p = 0.0163) were also significantly more frequent in affected compared to healthy siblings and A2Cw- (p = 0.0445) among the latter. No HLA genetic linkage with a putative LCL susceptibility gene(s) could be demonstrated in this study. A case/control comparison of 26 unrelated LCL patients (one proband from each family) and healthy individuals of the same ethnic origin confirmed the association of HLA-Bw22 (pc = 0.048) and -DQw3 (pc = 0.036) with LCL. The relative risk reached 12.5 for Bw22 and 4.25 for DQw3 with ethiologic factors of 0.17 and 0.64, respectively. HLA-DQw3 apparently makes the major contribution as a genetic risk factor for LCL at the population level.