Iloperidone is an atypical antipsychotic in development for the treatment of schizophrenia. This report examines efficacy results from three 6-week, randomized, double-blind, placebo- and active comparator-controlled studies in patients with schizophrenia or schizoaffective disorder. Multiple doses of iloperidone were studied. Active comparators (haloperidol 15 mg/d, or risperidone 4-8 mg/d) were included to confirm trial validity. The primary protocol-defined efficacy variable in Study 1 was change from baseline to end point in Positive and Negative Syndrome Scale total scores; in Studies 2 and 3, it was change in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale scores. Results were assessed through analysis of covariance using last observation carried forward in the intent-to-treat population. In total, 1943 patients were randomized. At least 1 iloperidone dosing group in each study demonstrated significantly better efficacy than placebo (Study 1, iloperidone 12 mg/d [P = 0.047]; Study 2, 4-8 mg/d [P = 0.012] and 10-16 mg/d [P = 0.001]; and Study 3, 20-24 mg/d [P = 0.010]). Active controls were also significantly more effective than placebo in each trial, thus validating the trials. Additional analysis in patients who received active treatment for at least 2 weeks indicated comparable efficacy score reductions at 6 weeks for patients receiving iloperidone 20 to 24 mg/d versus those receiving haloperidol or risperidone. Risk for motor-related adverse events (eg, akathisia and extrapyramidal symptoms) was lower with iloperidone than with risperidone and haloperidol and was generally similar to placebo. These trials indicate that iloperidone is effective for the treatment of schizophrenia.