Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that regulates adipocyte differentiation. Variations in the PPARgamma gene may affect the function of the PPARgamma and, therefore, body adipocity. We investigated the frequencies of the Pro12Ala polymorphism in exon B and the silent CAC478CAT polymorphism in exon 6 of the PPARgamma gene and their effects on body weight, body composition, and energy expenditure in obese Finns. One hundred and seventy obese subjects [29 men and 141 women; body mass index (BMI), 35.7 +/- 3.8 kg/m2; age, 43 +/- 8 yr; mean +/- SD) participated in the study. The frequencies of the Ala12 allele in exon B and CAT478 allele in exon 6 were not significantly different between the obese and population-based control subjects (0.14 vs. 0.13 and 0.19 vs. 0.21, respectively). The polymorphisms were associated with increased BMI [Pro12Pro, 34.5 +/- 3.8; Pro12Ala, 34.8 +/- 3.1; Ala12Ala, 39.2 +/- 4.6 kg/m2 (P = 0.011); CAC478CAC, 34.5 +/- 3.8; CAC478CAT, 34.5 +/- 3.3; CAT478CAT, 37.7 +/- 4.1 kg/m2 (P = 0.046)]. In addition, the women with both Ala12Ala and CAT478CAT genotypes (n = 5) were significantly more obese compared with the women having both Pro12Pro and CAC478CAC genotypes (n = 85; BMI, 40.6 +/- 3.3 vs. 34.4 +/- 3.9 kg/m2; P = 0.001), and they had increased fat mass (46.8 +/- 9.1 vs. 36.8 +/- 7.5 kg; P = 0.005). In conclusion, the Pro12Ala and CAC478CAT polymorphisms in the PPARgamma gene are associated with severe overweight and increased fat mass among obese women.