The peroxisome proliferator-activated receptor (PPAR)-gamma2 gene polymorphism Pro12Ala has been associated with increased insulin sensitivity in some but not all studies. Little is known about its effect on the tracking of insulin resistance status over time. These aspects were examined in a community-based sample of 686 white young adults, aged 20-38 years, and 426 white children, aged 4-17 years, and a subsample of a cohort (n = 362) who participated both as children and adults, with an average follow-up period of 13.4 years. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR) using fasting insulin and glucose. The frequency of the variant Ala12 allele was 0.104 in whites vs. 0.017 in blacks. After adjusting for sex, age, and BMI, adult subjects with the genotype Pro/Pro, Pro/Ala, and Ala/Ala, respectively, showed significant decreasing trends in fasting insulin (11.7, 10.3, and 8.8 micro U/ml; P = 0.002) and HOMA-IR (2.4, 2.1, and 1.7; P = 0.006). Similar but nonsignificant trends were noted in childhood. A significant genotype-BMI interaction effect on insulin (P = 0.020), glucose (P = 0.007), and HOMA-IR (P = 0.001) was found in adulthood, with carriers versus noncarriers showing attenuated association with BMI. The genotype-BMI interaction effect on these variables tended to be similar in childhood. With respect to tracking over time, of individuals in the top age- and sex-specific quartile of HOMA-IR in childhood, 48.7% (38/78) of noncarriers vs. 16.7% (2/12) of the carriers (P = 0.035) remained in the same quartile in adulthood. A similar trend was observed for insulin (2/13 vs. 35/77, P = 0.037). In conclusion, the Pro12Ala polymorphism of the PPAR-gamma2 gene beneficially influences insulin resistance and its tracking from childhood to adulthood. Further, the Ala12 allele attenuates the adverse association between adiposity and insulin resistance measures.