Tuberculoid (TT) and lepromatous leprosy (LL) develop in the human host depending on his ability to trigger a specific cellular immune response(CIR). Different genes have been demonstrated in susceptibility/protection and may explain the forms of leprosy. The major histocompatibility complex (MHC) play an important role. The aim of the study was to explore the contribution of human leukocyte antigen (HLA) DRB1, DQA1, DQB1 and DQ promoter genes in LL Mexican patients. Six families (26 LL, three TT patients and 27 controls) were analyzed; 114 unrelated patients were compared with 204 controls. Class I typing was done by the standard microlymphocytotoxicity and class II typing using PCR-SSOP. Haplotype segregation correlated with specific CIR in vivo and in vitro using lepromin. Haplotype sharing was significantly deviated in the affected sibs (p=0.01). Six healthy sibs were non-responders to lepromin and four of them were DQ1 homozgotes. DQ1 was significantly associated with LL and with non-responders. We set up macrophage activation experiments after infecting these cells with 5×10⁶ bacilli to demonstrate if elimination occurred in the context or DQ1. When DQ1 was present on macrophages and on T cells, bacteria were poorly eliminated from the cell (32%) while when absent, 76% of the individuals were able to eliminate the bacilli (p=0.03). DRB1*1501 DQA1*0102-DQB1*0602 (DQ1 subtype) was significantly increased in the patients, indicating its participation in susceptibility. QBP 5.11/5.12 promoter present in the mentioned haplotype, and QAP 1.4, linked to DRB1*1301/02 haplotypes were also associated. Two mechanisms are suggested: the promoter polymorphisms may influence allele expression and thus the amount of peptides presented to the T-cell receptor, leading to a deficient CIR: HLA restriction is important for vaccine design; the way peptides anchor the DRB1*1501 groove may be relevant to the activation of TH1 cells, which contribute to an efficient presentation of peptides inducing a protective T-cell response.