CONTEXT: Fat redistribution, insulin resistance, and low-grade inflammation characterize HIV-infected patients with lipodystrophy. Currently, no effective therapies exist for the combined treatment of fat redistribution and insulin resistance. OBJECTIVE: Our objective was to evaluate the effects of strength and endurance training on insulin sensitivity and fat distribution in HIV-infected patients with lipodystrophy. SUBJECTS AND METHODS: Twenty sedentary HIV-infected men with lipodystrophy were randomly assigned to supervised strength or endurance training three times a week for 16 wk. The primary endpoints were improved peripheral insulin sensitivity (euglycemic-hyperinsulinemic clamp combined with isotope-tracer infusion) and body fat composition (dual-energy x-ray absorptiometry scan). Secondary endpoints included fasting lipids and inflammatory markers. RESULTS: Insulin-mediated glucose uptake increased with both endurance training (55.7 +/- 11 to 63.0 +/- 11 micromol glucose/kg lean mass.min, P = 0.02) and strength training (49.0 +/- 12 to 57.8 +/- 18 micromol glucose/kg lean mass.min, P = 0.005), irrespective of training modality (P = 0.24). Only strength training increased total lean mass 2.1 kg [95% confidence interval (CI), 0.8-3.3], decreased total fat 3.3 kg (95% CI, -4.6 to -2.0), trunk fat 2.5 kg (95% CI, -3.5 to -1.5), and limb fat 0.75 kg (95% CI, -1.1 to -0.4). Strength training significantly decreased total and limb fat mass to a larger extent than endurance training (P < 0.05). Endurance training reduced total cholesterol, low-density lipoprotein cholesterol, free fatty acids, high-sensitivity C-reactive protein, IL-6, IL-18, and TNF-alpha and increased high-density lipoprotein cholesterol, whereas strength training decreased triglycerides, free fatty acids, and IL-18 and increased high-density lipoprotein cholesterol (P < 0.05 for all measurements). CONCLUSION: This study demonstrates that both strength and endurance training improve peripheral insulin sensitivity, whereas only strength training reduces total body fat in HIV-infected patients with lipodystrophy.