Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.