Using self-report of race/ethnicity, African Americans consistently have a higher prevalence of peripheral artery disease (PAD) compared to other ethnic groups. We aimed to determine the associations between estimated genetic admixture and PAD among African and Hispanic Americans. We studied the association between genetic ancestry and PAD among 1417 African and Hispanic American participants in the Multi-Ethnic Study of Atherosclerosis who were genotyped for ancestry informative markers (AIMs). PAD was defined as an ankle-brachial index (ABI) < 0.90. The overall prevalence of PAD among the 712 self-identified African American subjects was 15.2% and 4.6% among the 705 self-identified Hispanic Americans. A one standard deviation increment in European ancestry was associated with non-significant reductions in the odds for PAD among African (OR: 0.96 [95% CI: 0.78-1.18]) and Hispanic Americans (0.84 [0.58-1.23]), while the same increment in Native American ancestry was significantly associated with a lower odds of PAD in Hispanic Americans (0.56 [0.36-0.96]). Adjustment for demographic variables, field center, cardiovascular disease (CVD) risk factors and inflammatory markers strengthened the odds for European ancestry among African (0.85 [0.66-1.10]) and Hispanic Americans (0.68 [0.41-1.11]). The magnitude of the association for Native American ancestry among Hispanic Americans did not materially change (0.56 [0.29-1.09]). In conclusion, a higher percent Native American ancestry in Hispanics is associated with a lower odds of PAD while in both Hispanics and African Americans, greater European ancestry does not appear to be associated with lower odds for PAD.