Changes in glucose and fat metabolism associated with human immunodeficiency virus (HIV) infection have received attention because of the development of glucose intolerance, dyslipidemia, and lipodystrophy associated with protease inhibitor (PI) therapy. The response to ingested [13C]glucose (1.4 g/kg) was determined in 9 asymptomatic male HIV patients before and after 4.8 months of PI therapy (nelfinavir, 2,250 mg/d) compared with 9 matched seronegative HIV controls. No significant difference was observed for basal plasma glucose, insulin, and C-peptide concentrations between controls and patients before PI therapy. After 4.8 months of PI therapy, basal plasma glucose concentration was slightly, but significantly, increased (approximately 15%) compared with controls or HIV patients prior to receiving PI therapy. Over the first hour following ingestion of the glucose load, plasma glucose and insulin concentrations were higher in HIV patients than in controls, both before (approximately 15% and approximately 29%, respectively) and after (approximately 32% and approximately 43%, respectively) PI therapy. In addition, plasma C-peptide concentration was approximately 61% higher after PI therapy. The oxidation rate of fat, endogenous, and exogenous glucose was computed from the VO2 and respiratory exchange ratio corrected for protein oxidation and from 13C/12C in expired CO2. The only difference between controls and patients both before and after PI therapy was observed over the first 120 minutes following ingestion of the glucose load, when HIV patients oxidized approximately 18% more glucose and approximately 19% less fat than controls. This was not due to a larger oxidation rate of exogenous glucose, but to a larger oxidation rate of endogenous glucose (approximately 50%) in patients compared with controls. These data indicate that HIV infection is associated with minor changes in glucose metabolism, and that PI therapy with nelfinavir for 4.8 months only slightly further impairs glucose metabolism as assessed in response to a large oral glucose load. However, the larger stimulation of total and endogenous glucose oxidation and the larger reduction in fat oxidation, observed in the metabolic response to the glucose load in HIV patients, over time, could result in the accumulation of body fat and could contribute to lipodystrophy.