The objective of this study was to compare the level of insulin resistance, estimated by fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR), between Mexican Pima Indians and U.S. Pima Indians. For that purpose, analyses were conducted on 194 Mexican Pima Indians (100 women, 94 men) and 449 U.S. Pima Indians (246 women, 203 men) with normal glucose tolerance. Results showed that Mexican Pima Indians were less insulin resistant than their counterpart U.S. Pima Indians, even after adjusting for age, sex and obesity. However, part of the differences in insulin resistance between groups was explained by the greater degree of obesity in the U.S. Pima Indians because this difference was attenuated by about 40% after adjusting for obesity but still remained statistically significant. Accordingly, the increased physical activity in Mexican Pima also explained part of the differences in insulin resistance. Thus, these results confirm the strong contribution of lifestyle factors in protecting against insulin resistance even in genetically predisposed populations.