The objective of our study was to define the pharmacokinetics and pharmacodynamics of megestrol acetate in patients with human immunodeficiency virus (HIV) infection. A new suspension formulation of megestrol acetate (40 mg/ml) was administered as a single oral dose of 800 mg per day in an open label pharmacokinetic study for 21 days. On day 21 of therapy, patients were evaluated for changes in body weight and plasma samples were obtained for steady-state pharmacokinetic analysis. Ten HIV-infected men with an involuntary weight loss of >10% baseline were evaluated. A high degree of interpatient variability in megestrol acetate pharmacokinetics was observed, with an 8− and 5-fold range in the rate and extent of absorption, respectively. All patients reported an increase in appetite, and 8 of 10 patients gained weight by 3 weeks; the median change in weight in all patients at 3 weeks was a 1.8-kg gain (range: 2.3-kg loss to 6.4-kg gain). The two patients who did not gain weight had the lowest area under the curve (AUC), Cmax, and Cminvalues. A statistically significant correlation between the ratio of body weight at 3 weeks/initial weight (weight index) and the percentage of the 24-h dosing interval that megestrol acetate concentrations exceeded a 300-ng/ml threshold was observed. These data indicate variable levels of systemic exposure to drug following a fixed dose of a suspension formulation of megestrol acetate. Increase in weight during the early stages of megestrol acetate therapy is related to the extent of in vivo drug exposure above a threshold concentration. Dose individualization may be required for weight gain in AIDS with megestrol therapy.