Recent research suggests that the Pro12Ala variant in peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) is associated with diabetes- and obesity-related traits, and that its effects may be modified by obesity status. We characterized this variant in a population-based sample of 1,441 middle-aged African-American individuals with respect to diabetes-, obesity-, and other cardiovascular-related traits, both cross-sectionally and prospectively. The overall frequency of Ala12 was 1.9% (95% CI 1.5-2.5%), significantly lower than in Caucasian populations. Consistent with previous findings in Caucasians, African Americans with type 2 diabetes tended to be less likely to have the Pro/Ala genotype than those without (odds ratio [OR] 0.64, 95% CI 0.34-1.20); however, this OR was not statistically significant. Among nonobese individuals, the Pro/Ala genotype was associated with significantly lower ln(insulin) (P = 0.001), lower ln(HOMA-IR) (homeostasis model assessment of insulin resistance) (P = 0.002), higher fasting glucose-to-insulin ratio (P = 0.005), and lower diastolic blood pressure (P = 0.02). Among overweight individuals (BMI 25-29.9 kg/m(2)), the Pro/Ala genotype was associated with greater BMI (P = 0.02), waist-to-hip ratio (P = 0.01), and waist circumference (P = 0.04). Among obese individuals, there was no association between any of the diabetes- or obesity-related traits and the Pro12Ala PPAR-gamma2 variant. We conclude that among nonobese African Americans, the Pro/Ala genotype is associated with markers of greater insulin sensitivity.