Abstract Limited data on sex differences in body composition changes in response to higher protein diets (PRO) compared to higher carbohydrate diets (CARB) suggest that a PRO diet helps preserve lean mass (LM) in women more so than in men. Objective To compare male and female body composition responses to weight loss diets differing in macronutrient content. Design Twelve month randomized clinical trial with 4mo of weight loss and 8mo weight maintenance. Subjects Overweight (N = 130; 58 male (M), 72 female (F); BMI = 32.5 ± 0.5 kg/m2) middle-aged subjects were randomized to energy-restricted (deficit ~500 kcal/d) diets providing protein at 1.6 g.kg-1.d-1 (PRO) or 0.8 g.kg-1.d-1 (CARB). LM and fat mass (FM) were measured using dual X-ray absorptiometry. Body composition outcomes were tested in a repeated measures ANOVA controlling for sex, diet, time and their two- and three-way interactions at 0, 4, 8 and 12mo. Results When expressed as percent change from baseline, males and females lost similar amounts of weight at 12mo (M:-11.2 ± 7.1 %, F:-9.9 ± 6.0 %), as did diet groups (PRO:-10.7 ± 6.8 %, CARB:-10.1 ± 6.2 %), with no interaction of gender and diet. A similar pattern emerged for fat mass and lean mass, however percent body fat was significantly influenced by both gender (M:-18.0 ± 12.8 %, F:-7.3 ± 8.1 %, p