The present study sought to investigate, in sedentary men and women, (a) whether a common functional gene variant (peroxisome proliferator–activated receptor-γ2 [PPARγ2] Pro12Ala) predicts insulin action and (b) whether improvements in insulin action in response to endurance exercise training are associated with PPARγ2 Pro12Ala. Sedentary, 50- to 75-year-old men and women (N = 73) were genotyped and underwent oral glucose tolerance tests (OGTTs) before and after 6 months of endurance training. At baseline, men heterozygous for the Pro12Ala variant had a greater OGTT insulin area under the curve (AUC) as compared with Pro12 homozygous men (P = .009). Endurance training resulted in a significantly greater improvement in insulin AUC in Pro12Ala heterozygous men as compared with Pro12 homozygous men (P = .003) despite no genotype-specific differences with respect to training-induced changes in body weight, body mass index, and percent body fat. No differences between genotype groups were present at baseline or in response to training in women. Training did not alter the OGTT glucose AUC for the group as a whole, and the baseline, final, and change in glucose AUC were not dependent on PPARγ2 genotype and/or sex. In conclusion, these findings suggest that sedentary men with the PPARγ2 Pro12Ala variant have lower insulin action on glucose disposal as compared with their counterparts. However, these men are particularly responsive with respect to the magnitude of endurance training–induced improvement in insulin action.