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Objective: To evaluate the efficacy of ondansetron for the treatment of schizophrenia.Data Sources: Searches of MEDLINE (1950–March 2010) and Google Scholar were performed. Key search terms included ondansetron, Zofran, serotonin antagonists, 5-HT, serotonin receptor, and schizophrenia.Study Selection and Data Extraction: All articles published in English identified from the data sources were evaluated. All studies and case reports evaluating ondansetron for the treatment of schizophrenia were reviewed.Data Synthesis: Six clinical trials, including 3 double-blind, randomized trials, and 2 case reports pertinent to ondansetron use in schizophrenia, were identified. Ondansetron daily doses ranged from 4 to 16 mg, with doses administered once or twice daily. Ondansetron was used as monotherapy in 3 trials and as an adjunct to therapy with clozapine, haloperidol, or risperidone, respectively, in 3 trials. Studies were of varying durations, ranging from a single-dose study with a 3-hour follow-up to three 12-week studies. Most studies evaluated ondansetron's efficacy in treating schizophrenia as measured with changes in Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale, and Clinical Global Impression scale scores. In the 2 largest trials, with a combined patient population of 151, treatment with adjunctive ondansetron resulted in statistically significant improvement in negative symptoms as assessed with PANSS. In all studies, ondansetron was well tolerated, with no severe adverse reactions reported.Conclusions: Ondansetron may be effective as an adjunct to antipsychotics for the treatment of schizophrenia, specifically negative symptoms, as assessed with PANSS. Due to the variation in concurrent therapies and dosing regimens, it is difficult to establish an optimal dose from the reviewed trials. Further large, randomized, double-blind, active-controlled studies would be helpful in determining the role of ondansetron in the treatment of schizophrenia.