Few studies have addressed the association of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2) gene with longitudinal measures of adiposity and insulin sensitivity during young adulthood, or reported on its relationship with these outcomes in African Americans. These issues were examined in the biracial Coronary Artery Risk Development in Young Adults (CARDIA) cohort, a population-based sample of 5115 African Americans and whites followed prospectively over 15 years. Frequency of the Ala12 allele was 2.1% in African Americans and 12.8% in whites, consistent with previous reports. A generalized estimating equation method was used to simultaneously examine the cross-sectional and longitudinal relationships between the Pro12Ala polymorphism and the measures of adiposity and insulin sensitivity. The Pro12Ala polymorphism was significantly associated with mean 15-year levels of adiposity, but these associations were in opposite direction in the 2 racial groups. On average, African Americans carrying the Ala12 allele had a 1.1 kg/m2 lower body mass index (BMI) ( P = .02) and whites a 0.6 kg/m2 higher BMI ( P = .01), as compared to Pro12 homozygotes. The Ala12 allele was also significantly associated with a decreased risk of incident insulin resistance syndrome in each race (OR = 0.44, P = .04 in African Americans; OR = 0.61, P = .01 in whites) and lower mean 15-year levels of fasting insulin ( P = .02), glucose ( P = .02), and homeostasis model assessment ( P = .01) in African Americans but not in whites. Important roles of BMI and ethnic background in influencing the complex relationships among PPAR gamma gene variation, adiposity, and insulin resistance are suggested.