Rifapentine uptake by human peritoneal macrophages and polymorphonuclear leukocytes was evaluated and its activity against intracellular Staphylococcus aureus and Staphylococcus epidermidis in both types of phagocytes was compared to that of rifampin, teicoplanin and clindamycin. Uptake of radiolabeled rifapentine by peritoneal macrophages (intracellular/extracellular ratio 61.4 +/- 5.8) and polymorphonuclear leukocytes (intracellular/extracellular ratio 87.6 +/- 3.9) was significantly higher than that of teicoplanin (intracellular/extracellular ratio 40.8 +/- 3.6 and 52.3 +/- 3.2 respectively) and clindamycin (intracellular/extracellular ratio 6.9 +/- 0.4 and 8.3 +/- 0.5 respectively). Rifapentine and rifampin showed the highest activity against intracellular staphylococci in both peritoneal macrophages and polymorphonuclear leukocytes. Clindamycin also showed efficient intracellular activity. In contrast, teicoplanin, which achieved high cellular levels with both types of phagocytes, failed to produce a significant reduction in viable intraphagocytic Staphylococcus epidermidis. On the basis of these findings it is suggested that rifapentine may play a future role in the treatment of certain types of staphylococcal infection.