OBJECTIVE A recent in vitro study has shown that risperidone is a substrate of P-glycoprotein. The aim of this study was to confirm the effects of verapamil, a P-glycoprotein inhibitor, on the pharmacokinetics of risperidone. METHODS Two 6-day courses of either 240 mg verapamil daily, an inhibitor of P-glycoprotein, or placebo were administered in a randomized crossover fashion with at least a 4-week washout period. Twelve male volunteers took a single oral 1-mg dose of risperidone on day 6 of both courses. Plasma concentrations of risperidone, 9-hydroxyrisperidone, and prolactin were monitored up to 24 hours after dosing. RESULTS Compared with placebo, verapamil treatment significantly increased the peak plasma concentration of risperidone by 1.8-fold and the area under the plasma concentration-time curve (AUC) from 0 to 24 hours of risperidone by 2.0-fold but did not alter the elimination half-life. The AUC from 0 to 24 hours of 9-hydroxyrisperidone, but not other pharmacokinetic parameters, was significantly increased during verapamil treatment. However, the AUC from 0 to 4 hours and the AUC from 0 to 8 hours of prolactin concentrations were not increased by verapamil treatment despite the pharmacokinetic alterations. CONCLUSIONS This study demonstrated that the bioavailability of risperidone was increased by verapamil, suggesting in vivo involvement of P-glycoprotein in the pharmacokinetics of risperidone.