Many drugs have been associated with QTc prolongation and, in some cases, this is augmented by concomitant administration with metabolic inhibitors. The effects of 6 antipsychotics on the QTc interval at and around the time of estimated peak plasma/serum concentrations in the absence and presence of metabolic inhibition were characterized in a prospective, randomized study in which patients with psychotic disorders reached steady-state on either haloperidol 15 mg/d (n = 27), thioridazine 300 mg/d (n = 30), ziprasidone 160 mg/d (n = 31), quetiapine 750 mg/d (n = 27), olanzapine 20 mg/d (n = 24), or risperidone 6-8 mg/d increased to 16 mg/d (n = 25/20). Electrocardiograms (ECGs) were done at estimated Cmax at steady-state on both antipsychotic monotherapy and after concomitant administration of appropriate cytochrome P-450 (CYP450) inhibitor(s). Mean QTc intervals did not exceed 500 milliseconds in any patient taking any of the antipsychotics studied, in the absence or presence of metabolic inhibition. The mean QTc interval change was greatest in the thioridazine group, both in the presence and absence of metabolic inhibition. The presence of metabolic inhibition did not significantly augment QTc prolongation associated with any agent. Each of the antipsychotics studied was associated with measurable QTc prolongation at steady-state peak plasma concentrations, which was not augmented by metabolic inhibition. The theoretical risk of cardiotoxicity associated with QTc prolongation should be balanced against the substantial clinical benefits associated with atypical antipsychotics and the likelihood of other toxicities.