Weight loss is known to impact survival among patients infected with human immunodeficiency virus (HIV) even in the era of highly active antiretroviral therapy (HAART). In a randomized trial, we compared the effects of 2 months of treatment with either megestrol acetate (800 mg every day) or oxandrolone (10 mg twice per day) on body weight and composition in patients with weight loss of > or =5 kg who were receiving HAART. The mean weight was 66 kg, and the mean body mass index was 21. Mean weight gain in the megestrol acetate and the oxandrolone arms were 2.8 kg (4.6% of the baseline value) and 2.5 kg (3.9% of the baseline value), respectively (P=.80). Lean body mass accounted for 39% of weight gain in the megestrol acetate arm and 56% in the oxandrolone arm (P=.38). Seven patients in the megestrol acetate arm and 5 patients in the oxandrolone arm reported minor adverse events (P=.74). In conclusion, megestrol acetate therapy and oxandrolone therapy have similar effects on body weight and composition and are safe and well-tolerated during HAART.