Genetic predisposition to both disease susceptibility and to host immune response has been postulated. In India, about 64% of leprosy prevalence and 78% of new case detection of the worlds estimated 719,330 cases occur. Convincing results have been reported from studies on HLA class II association in leprosy. However data on HLA class I association are limited and inconsistent. The HLA A, B and C allele distribution in 103 leprosy patients and 101 normal healthy control individuals were studied by microlymphocytotoxicity assay. Further 32 multibacillary leprosy patients along with the 67 controls were studied by molecular high-resolution PCR-SSOP technique. The significant results from the present study were: 1) serologically, a significant increase in HLA A2, A11, B40 and Cw7, while a decrease of A28, B12, B15 and Cw3 were observed among the leprosy patients when compared with the controls; 2) molecular subtyping in multibacillary leprosy patients revealed a significant increase in frequency of HLA A*0203, A*0206, A*1102, B*1801, B*4016, B*5110, Cw*0407 and Cw*0703 while a decrease in the frequency of HLA A*0101, A*0211, B*4006, Cw*03031, Cw*04011 and Cw*0602 leprosy patients was observed when compared with the controls; 3) further haplotypes A*1102-B*4006-Cw*1502; A*0203-B*4016-Cw*0703; A*11-B*40 was significantly increased among the multibacillary leprosy patients when compared with the controls. It seems that HLA class I alleles play vital roles in disease association/pathogenesis.