Localized cutaneous leishmaniasis (LCL) is the prevalent form of leishmaniasis in Mexico. It is limited to the skin; reversible upon treatment and the host cellular immune response is intact. Several genes that influence the expression of LCL have been described in the mouse. In humans, we, as well as others, have demonstrated that HLA-DQ3 antigens seem to play some role in host susceptibility. We therefore analyzed at the DNA level, the class II loci of the same patients that were previously studied by serology. The purpose of this study was to assess the contribution of HLA DR, DQ, and DP genes in the protection and/or the susceptibility to LCL. Sixty-five patients with LCL from Comalcalco, state of Tabasco, were recruited and 100 healthy controls were included for comparison. All were Mexican Mestizos. DRB1, DQA1, DQB1, DPA1, and DPB1 alleles were typed using two different methods: PCR-SSO and PCR-SSP. Results indicate that class II genes are relevant for the expression of LCL and several loci contribute independently and sinergically. DRB1*0407 participates in susceptibility with an etiological fraction (EF) of 20% and an odds ratio (OR) of 2.92. Two additional susceptibility genes were found. These are located to the DP locus: DPA1*0401 (OR = 10.07; EF=7%) and DPB1*0101 (OR = 5.99 EF = 13%). Resistance was found associated to DPB1*0401, thus *0401 "motif" could be an ideal candidate for the development of a vaccine. DR2 (DRB1*1500+DRB1*1600) has also a significant p for protection, suggesting that the sequence common to this group of antigens may anchor parasite peptides which trigger a protective response.