BACKGROUND: The use of antiretroviral combination therapy in HIV has been associated with lipodystrophy and cardiovascular risk factors. OBJECTIVE: To compare the effects of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone and metformin for treating HIV lipodystrophy. DESIGN: An open, randomized, 6-month clinical trial. SETTING: University Medical Center, Utrecht, the Netherlands. PATIENTS: 39 HIV-infected men with lipodystrophy. INTERVENTION: Rosiglitazone, 8 g/d, or metformin, 2 g/d [DOSAGE ERROR CORRECTED] MEASUREMENTS: Insulin sensitivity estimated by the oral glucose tolerance test, subcutaneous and visceral abdominal fat measured by single-slice computed tomography, endothelial function measured by flow-mediated vasodilation, and fasting plasma measurements. Two patients in the metformin group withdrew from the study. Complete case analysis was performed. RESULTS: Compared with metformin, rosiglitazone increased subcutaneous abdominal fat (between-treatment change from baseline, 27 cm2 [95% CI, 7 cm2 to 46 cm2]) and visceral abdominal fat (between-treatment change from baseline, 24 cm2 [CI, 6 cm2 to 51 cm2]). The area under the curve for insulin after the oral glucose tolerance test decreased similarly with both agents, but only rosiglitazone increased adiponectin levels. Metformin showed greater benefits on fasting lipid profile than rosiglitazone. Flow-mediated vasodilation statistically significantly increased with metformin (mean change, 1.5% [CI, 0.4% to 3.3%]) and not with rosiglitazone (mean change, 0.7% [CI, -1.1% to 2.7%]). The metformin versus rosiglitazone increases did not statistically differ. Rosiglitazone and metformin did not change C-reactive protein levels. LIMITATIONS: This small trial was not blinded or placebo-controlled and did not measure clinical outcomes. CONCLUSIONS: The findings emphasize the importance of individualized care in HIV-infected patients. Although rosiglitazone may partly correct lipoatrophy, metformin improves visceral fat accumulation, fasting lipid profile, and endothelial function.