The IRF5 gene was found to be strongly associated with SLE. We identified two functional polymorphisms and recently an insertion/deletion together with a tag SNP defining the risk haplotype in individuals of European ancestry. We now analyzed sets of Mexican patients with SLE. Three polymorphisms in the IRF5 gene were genotyped in two sets of Mexican individuals with SLE and controls as well as in families including a set of pediatric SLE patients. A set of healthy Mexican Indians was also typed. Genetic association with SLE was found for all three polymorphisms. The genetic association was very strong in the case-control analysis in both sets (for SNP rs2070197, combined P = 1.26 x 10(-21)) and in families (combined P = 0.000004). Compared to healthy individuals with European ancestry, the frequency of the risk haplotype in healthy Mexican individuals was significantly higher and even higher in the healthy Mexican Indian group. Further, a much higher frequency of the risk haplotype and of individual homozygote for it was found among Mexican SLE patients. The significantly higher frequency of homozygote individuals for the risk haplotype among Mexican SLE patients could be the result of genetic admixture, and suggests the possibility that IRF5 could be involved in the more active disease and organ involvement known to occur among Mexican SLE patients.