Context. Testosterone increases fat-free mass (FFM) in HIV-infected men, but its effects on muscle performance, physical function, mood and quality of life are poorly understood. Methods: Sixty-one HIV-infected men with weight loss were randomized to receive weekly intramuscular injections of either 300mg testosterone enanthate or placebo for 16 weeks. The primary outcome of interest was physical function (walking speed, stair climbing power, load carrying ability). Secondary outcome measures included body weight and composition, muscle performance, sexual function, mood, and quality of life. Results: Serum nadir free and total testosterone levels increased (+188.0± 29.6 pg/mL and +720± 86 ng/dL) in the testosterone but not placebo group. Testosterone administration was associated with increased FFM (2.8 ± 0.5 kg) which was significantly greater than in the placebo group (p<0.0001). Leg press strength increased significantly in testosterone-treated (p=0.027) but not in placebo-treated men; the difference between groups was not significant. Other measures of muscle performance and physical function did not change significantly in either group. Men receiving testosterone demonstrated significantly greater improvements in mental health and quality of life scores than those receiving placebo, and improvements in fatigue/energy and mood scores which were not significantly different from placebo. Sexual function scores did not change in either group. Conclusions: In HIV infected men with weight loss, a supraphysiologic dose of testosterone significantly increased FFM, but did not improve self-reported or performance-based measures of physical function. Improvements in mood, fatigue, and quality of life measures in the testosterone group, though clinically important, need further confirmation.