It has been hypothesized that the greater prevalence of non-insulin-dependent diabetes mellitus (NIDDM) in Mexicans may be related to their greater degree of Amerindian genetic admixture (AGA). The aim of this unmatched case–control study was to correlate the prevalence of NIDDM with AGA in 10 Mexican Mestizo populations non-randomly selected by surname. A sample of 1,699 unrelated persons, >44 years and residing in the state of Nuevo León, was selected on the basis of paraphyletic or polyphyletic surnames and interviewed in the Instituto Mexicano del Seguro Social (IMSS). All subjects received a medical examination, and diabetes was diagnosed on the basis of World Health Organization criteria. Three genetic marker systems were analyzed, and the percentage of AGA was calculated. Logistic regression analysis was performed with the prevalence as the dependent variable and sex and surname as the independent variables. The Spearman rank–order correlation analysis was calculated between the age-adjusted prevalence (45–75+ years) and AGA. The correlation revealed a pattern of increasing prevalence of NIDDM with increasing Amerindian ancestry by surname. Am. J. Hum. Biol. 12:721–728, 2000. © 2000 Wiley-Liss, Inc.