The fat mass and obesity-associated (FTO) gene was genotyped for the participants in the Dose-Response to Exercise in postmenopausal Women (DREW) trial and analyses were performed to determine whether an FTO variant was associated with adiposity and cardiorespiratory fitness (CRF) before and after 6 months of moderate intensity exercise in white women (n = 234). The A/A homozygotes for rs8050136 had a higher BMI (kg/m(2)) compared to C/C homozygotes at baseline (32.8 (0.6) vs. 31.0 (0.4), respectively; P < 0.05) and at follow-up (31.9 (0.6) vs. 30.4 (0.5), respectively; P < 0.05). Weight loss occurred after exercise, but there was no significant genotype by exercise interaction over time. Exploratory analyses among women exposed to moderate intensity exercise meeting, or exceeding, the physical activity recommendation found that those homozygous A/A lost significantly more weight than the C allele carriers (-3.3 (0.7) kg vs. -1.4 (0.4) kg and -1.5 (0.5) kg, respectively; P < 0.05). CRF, defined as VO(2peak) (oxygen consumption), increased after exercise and the magnitude of the increase was similar for each genotype. In conclusion, women genetically predisposed to being obese experienced weight loss and CRF benefits with moderate intensity exercise, with additional weight loss observed when the women met or exceeded the physical activity recommendations.