Objective: Hispanic populations typically show a high prevalence of dyslipidemias, especially of low high-density lipoproteins (HDLs) or HDL cholesterol. Highly admixed populations are ideal groups to clarify the role of genetic ancestry on HDL concentrations, isolating it from that of other factors. The objective of this study was to estimate the association between Native American genetic ancestry and HDL-cholesterol levels independent of socioeconomic factors in a representative sample of the Mexican population. Methods: We used data from the Mexican National Health Survey 2000, analyzing 1647 subjects from whom stored DNA samples and HDL measurements were available. To estimate proportional genetic ancestry (Native American, African, and European), we used a 107 genetic ancestry informative marker panel with the software STRUCTURE. To estimate the association between genetic ancestry and low HDL levels, we fitted logistic regression models with the percentage of Native American genetic ancestry, in quartiles, as the main predictor. Results: Mean HDL levels were 38.9 mg/dL, with 62% of subjects having levels below 40 mg/dL. Participants had on average 53.6% Native American, 39% European, and 7.3% African genetic ancestry. Those in the fourth quartile of Native American genetic ancestry had 35% higher odds of having low HDLcholesterol relative to those in the first quartile (odds ratio, 1.35; 95% confidence interval, 0.99-1.81) after adjustment for socioeconomic level and other covariates, although the association is clearly nonlinear. Conclusion: Native American genetic ancestry seems to play a small but distinct role in the development of low HDL cholesterol levels.