The combined effects of exercise and energy restriction on changes in body fat and fat-free mass (FFM) are controversial. This study was conducted to determine whether muscle hypertrophy is possible during weight loss. Fourteen obese females received a 3360-kJ/d liquid diet for 90 d. Seven subjects received a weight training (WT) regimen and seven subjects remained sedentary (C). Biopsy samples were obtained from the vastus lateralis muscle at baseline and after 90 d of treatment. The average weight loss over the 90-d period was 16 kg with ≈24% of the weight loss from FFM and 76% from fat. The amount and composition of the weight loss did not differ between WT and C groups. The cross-sectional area of slow twitch and fast twitch fibers was unchanged by treatment in C subjects but significantly increased in WT subjects. It appears that weight training can produce hypertrophy in skeletal muscle during severe energy restriction and large-scale weight loss.