Inadequate dietary patterns and sedentary lifestyles are believed to be important factors in predisposing people to obesity. This study analyzed the potential interaction between habitual physical activity and the carbohydrate (CHO)-fat distribution in 2 hypocaloric diets and the impact of such interplay on body composition changes. Forty healthy obese women, 20-50 years old, were randomly assigned to a high- or low-CHO energy-restricted diet, which was low or high in fat, respectively, during 10 weeks. Baseline and final measurements were performed to assess dietary habits, resting metabolic rate, and body composition changes. Physical activity was measured with a triaxial accelerometer and with a questionnaire. There were no significant differences in anthropometric and metabolic variables between both dietary groups at baseline. However, there was a positive correlation between total free-living physical activity and arm muscle preservation after 10 weeks (r = 0.371; p = 0.024). Interestingly, an interaction between macronutrient (CHO-fat distribution) intake and physical activity was found, since less-active subjects with a high-CHO-low-fat diet showed a greater fat loss than those more active with a lower-CHO-high-fat diet, whereas more-active subjects with a high-CHO-low-fat diet showed a smaller fat loss than those receiving a low-CHO-high-fat diet. Physical activity and the macronutrient content of energy-restricted diets, when designed to promote body fat mass reduction, should be considered together to better predict the outcome.