The objective of this project was to determine the association of the DQA1*0501 allele in the susceptibility to develop systemic lupus erythematosus (SLE) in Mexicans. Frequencies of generic MHC Class II genes (HLA-DR, DQA and DQB1) were determined by DNA typing in 58 Mexican mestizo SLE patients and 96 ethnically matched controls. Statistical analysis was performed by chi-square and Fisher's exact tests. The DQA1*0501 allele was found to be in linkage disequillibrium with H LA-DR3, DR11, and DR14. This explains the lack of association with the allele alone, and the evident strong association of SLE with the [HLA-DR3-DQA1*0501-DQB1*0201] and [HLA-DR1-DQA1*0101-DQB1*0501] haplotypes. It was also found a significant decrease (protection) of the [HLA-DR8-DQA1*0401-DQB1*0402] haplotype which is known to be a characteristic haplotype among the indigenous population of Mexico. These data shows that the susceptibility to SLE in Mexicans is more strongly influenced by the MHC haplotypes than by single alleles. The suggestion that these genes do not act alone but in combination, makes the identification of haplotypes mandatory.