Human immunodeficiency virus (HIV)-lipodystrophy syndrome (HLS) is characterized by hypertriglyceridemia, low high-density lipoprotein-cholesterol, lipoatrophy, and central adiposity. We investigated fasting lipid metabolism in six men with HLS and six non-HIV-infected controls. Compared with controls, HLS patients had lower fat mass (15.9 ± 1.3 vs. 22.3 ± 1.7 kg,P < 0.05) but higher plasma glycerol rate of appearance (R_a), an index of total lipolysis (964.71 ± 103.33 vs. 611.08 ± 63.38 μmol · kg fat⁻¹ · h⁻¹, P < 0.05), R_a palmitate, an index of net lipolysis (731.49 ± 72.36 vs. 419.72 ± 33.78 μmol · kg fat⁻¹ · h⁻¹, P < 0.01), R_a free fatty acids (2,094.74 ± 182.18 vs. 1,470.87 ± 202.80 μmol · kg fat⁻¹ · h⁻¹, P < 0.05), and rates of intra-adipocyte (799.40 ± 157.69 vs. 362.36 ± 74.87 μmol · kg fat⁻¹ · h⁻¹, P < 0.01) and intrahepatic fatty acid reesterification (1,352.08 ± 123.90 vs. 955.56 ± 124.09 μmol · kg fat⁻¹ · h⁻¹, P < 0.05). Resting energy expenditure was increased in HLS patients (30.51 ± 2.53 vs. 25.34 ± 1.04 kcal · kg lean body mass⁻¹ · day⁻¹, P < 0.05), associated with increased non-plasma-derived fatty acid oxidation (139.04 ± 24.17 vs. 47.87 ± 18.81 μmol · kg lean body mass⁻¹ · min⁻¹, P < 0.02). The lipoatrophy observed in HIV lipodystrophy is associated with accelerated lipolysis. Increased hepatic reesterification promotes the hypertriglyceridemia observed in this syndrome.