HIV infection and psychotic illnesses frequently coexist. The atypical antipsychotic olanzapine is metabolized primarily by CYP1A2 and glucuronosyl transferases, both of which are induced by the HIV protease inhibitor ritonavir. The purpose of this study was to determine the effect of ritonavir on the pharmacokinetics of a single dose of olanzapine. Fourteen healthy volunteers (13 men; age range, 20-28 years) participated in this open-label study. Subjects received olanzapine 10 mg and blood samples were collected over a 120-hour post-dose period. Two weeks later, subjects took ritonavir 300 mg twice daily for 3 days, 400 mg twice daily for 4 days, and 500 mg twice daily for 4 days. The next morning, after 11 days of ritonavir, olanzapine 10 mg was administered and blood sampling was repeated. Plasma samples were analyzed for olanzapine with HPLC. We compared olanzapine non-compartmental pharmacokinetic parameter values before and after ritonavir with a paired Student t test. Ritonavir reduced the area under the plasma concentration-time curve of olanzapine from 501 ng · hr/mL (443-582) to 235 ng · hr/mL (197-294) (p < 0.001), the half-life from 32 hours (28-36) to 16 hours (14-18) (p = 0.00001), and the peak concentration from 15 ng/mL (13-19) to 9 ng/mL (8-12) (p = 0.002). Olanzapine oral clearance increased from 20 L/hr (18-23) to 43 L/hr (38-51) (p < 0.001) after ritonavir. Ritonavir significantly reduced the systemic exposure of olanzapine in volunteers. Patients receiving this combination may ultimately require higher olanzapine doses to achieve desired therapeutic effects.