Combination antiretroviral therapy for the treatment of human immunodeficiency virus type 1-infected patients is associated with development of the lipodystrophy syndrome (LD). We previously showed that plasma levels of free fatty acids are higher in patients with lipodystrophy. The purpose of this study was to evaluate the postabsorptive rate of lipolysis, using [(2)H(5)]glycerol infusion, the resting energy expenditure (REE) measured by indirect calorimetry, and the responses of both to epinephrine infusion ( approximately 15 ng/kg.min) in patients with LD. Results were compared with those obtained in five matched human immunodeficiency virus type 1-infected patients. The postabsorptive rate of appearance of glycerol did not differ between the two groups. There was no difference in the lipolytic response to epinephrine, although the response in the LD group was delayed (P textless 0.001). The postabsorptive REE adjusted for lean body mass was lower and remained lower during epinephrine infusion in the LD group. Postabsorptive norepinephrine concentrations were higher and remained elevated during epinephrine infusion in the LD group. We conclude that the lipolytic response to epinephrine in the LD group was normal, albeit delayed. Norepinephrine concentrations were increased in patients with lipodystrophy, indicating increased sympathetic activity. Postabsorptive REE was lower in the patients with lipodystrophy. Our data suggest that highly active antiretroviral therapy-associated lipodystrophy normalizes the REE, but has only minor effects on lipolysis as a result of concomitant sympathetic stimulation of adipose tissue.