This study determined the effects of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala variant on body composition and metabolism and the magnitude of weight regain in 70 postmenopausal women (BMI 25-40 kg/m(2)) who completed 6 months of a hypocaloric diet. At baseline, BMI, percent body fat, intra-abdominal and subcutaneous abdominal fat areas, resting metabolic rate, substrate oxidation, and postprandial glucose and insulin responses were not different between genotypes (Pro/Pro = 56, Pro/Ala and Ala/Ala = 14). The intervention similarly decreased body weight by 8 +/- 1% in women homozygous for the Pro allele and by 7 +/- 1% in women with the Ala allele (P < 0.0001). Fat oxidation did not change in Pro/Pro women but decreased 19 +/- 9% in women with the Ala allele (P < 0.05). Changes in glucose area were not different between groups; however, women with the Ala allele decreased their insulin area more than women homozygous for the Pro allele (P < 0.05). Weight regain during follow-up was greater in women with the Ala allele than women homozygous for the Pro allele (5.4 +/- 0.9 vs. 2.8 +/- 0.4 kg, P < 0.01). PPAR-gamma2 genotype was the best predictor of weight regain (r = 0.50, P < 0.01), followed by the change in fat oxidation (partial r = 0.35, P < 0.05; cumulative r = 0.58). Thus, the Pro12Ala variant of the PPAR-gamma2 gene may influence susceptibility for obesity.