Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.