A genetic and epidemiological survey of non-insulin-dependent diabetes mellitus (NIDDM) was conducted among the Mexican Americans residing in three socioeconomically distinct areas of San Antonio, Texas: a low socioeconomic (SES) traditional area (barrio), a middle SES, ethnically balanced area (transitional), and a high SES, predominantly Anglo area (suburb). Seventeen polymorphic markers were used to relate the prevalences of NIDDM with the extent of Amerindian ancestry of 1,237 Mexican Americans of these three residential areas. While only the RH and haptoglobin loci showed evidence of association with NIDDM, an admixture analysis of the combined allele frequency data revealed a pattern of decreasing NIDDM prevalence with increasing socioeconomic status (as approximated by neighborhood of residence) and a parallel decrease in Amerindian ancestry. The rank-order correlation between NIDDM prevalence and Amerindian admixture is 0.943 (P less than .001) for the crude prevalence rate and 0.829 (P less than .02) for the age-adjusted rate. Nested gene diversity analysis revealed that the heterogeneity of allele frequencies is more pronounced when individuals were classified by their NIDDM disease status as compared to the classification by neighborhood. Estimation of Amerindian ancestry of each individual did not reveal any significant change in the shape of the distributions of individual admixture proportions in diabetics as compared to the controls. Nevertheless, the results suggest that genetic factors partially explain the differences in NIDDM prevalence observed between the Mexican American and Anglo populations in the southwestern United States.