The aim of this study was to investigate the efficacy and safety of ziprasidone in first-episode psychosis. This was an 8-week, open-label, multicenter trial. In total, 27 patients (14 male patients, 13 female patients) with a Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition diagnosis of schizophreniform disorder, schizoaffective disorder, schizophrenia, or psychotic disorder not otherwise specified comprised the study population. The initial recommended dose of ziprasidone was 40 mg/day. Within the first 2 weeks, the dose could be increased to 120–160 mg/day depending on the patient’s condition. The primary outcome variables were scores on the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity scale; secondary measures included the Calgary Depression Scale for Schizophrenia and others. To assess safety, we measured drug-related adverse events, weight, lipid variables, prolactin, and corrected QT (QTc) interval. Among the 27 enrolled participants, 16 dropped out [lack of efficacy (n=7), loss to follow-up (n=7), withdrawn consent (n=1), and serious adverse event (n=1)]. The mean total daily and endpoint doses of ziprasidone were 120.30±40.34 and 131.85±51.22 mg/day, respectively. The administration of ziprasidone resulted in significant improvement in the PANSS (P<0.0001) and CGI scores (P<0.0001) over time. Significant improvement in the Calgary Depression Scale for Schizophrenia score (P<0.0001) was also observed at week 8. The response rate (defined as a 30% or greater decrease in the PANSS total score from baseline to last observation) was 51.85%. No significant differences in extrapyramidal symptoms rating scale scores, and lipid and prolactin levels from baseline to last observation were found. However, modest side effects regarding the incidence of extrapyramidal symptoms and hyperprolactinemia, and weight change from baseline in male patients were observed. These results indicate that ziprasidone is effective in the treatment of the positive, negative, and depressive symptoms of first-episode psychosis and has a modest side-effect burden.