This research compared the long-term efficacy and safety of iloperidone with those of haloperidol in individuals with schizophrenia. Data were pooled from 3 prospective multicenter studies, each with 6-week stabilization followed by 46-week double-blind maintenance phases. Patients were randomized to iloperidone 4 to 16 mg/d or haloperidol 5 to 20 mg/d. Patients included in this analysis completed the initial 6-week phase with at least 20% reduction in Positive and Negative Syndrome Scale (PANSS) total score at weeks 4 and 6, had 7-item Clinical Global Impressions of Change (CGI-C) scores less than 4, received 1 or more doses of long-term phase medication, and had 1 or more efficacy/safety assessments during the long-term phase. The primary efficacy variable was time to relapse, defined as a 25% or more increase in PANSS total score, including at least a 10-point change; discontinuation because of lack of efficacy; aggravated psychosis with hospitalization; or 2-point increase in the 7-item CGI-C after week 6. Of 1644 patients randomized and 1326 completing the 6-week phase, 473 (iloperidone, n = 359; haloperidol, n = 114) were included in the long-term efficacy analysis, and 489 (iloperidone, n = 371; haloperidol, n = 118) in the safety analysis. Iloperidone was equivalent to haloperidol in time to relapse. The most common adverse events were insomnia (18.1%), anxiety (10.8%), and schizophrenia aggravated (8.9%) with iloperidone, and insomnia (16.9%), akathisia (14.4%), tremor (12.7%), and muscle rigidity (12.7%) with haloperidol. The Extrapyramidal Symptoms Rating Scale scores improved with iloperidone and worsened with haloperidol. Metabolic changes were minimal for both groups. Mean changes in Fridericia's QT interval correction were 10.3 msec (iloperidone) and 9.4 msec (haloperidol) at end point. Iloperidone demonstrated long-term efficacy equivalent to haloperidol and a favorable long-term safety profile, potentially making this agent a suitable option as maintenance therapy for schizophrenia.