Background Lurasidone is a new atypical antipsychotic agent with high affinity for D2, 5-HT2A and 5-HT7 receptors. The current study evaluated the safety and efficacy of lurasidone and ziprasidone in stable outpatients diagnosed with schizophrenia or schizoaffective disorder. Methods Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder that was chronic (≥6months duration) and stable were randomized to 21days of double-blind treatment with a fixed dose of lurasidone 120mg once daily (N=150) or ziprasidone 80mg BID (N=151). Changes from baseline in efficacy measures were evaluated using mixed model for repeated measures (MMRM) analyses. Results The proportion of patients who discontinued from the study was similar for lurasidone and ziprasidone (32.5% vs. 30.7%); the proportion who discontinued due to adverse events was similar (10.4% vs. 11.1%). Treatment with lurasidone and ziprasidone was associated with a small endpoint reduction in median weight (−0.65kg vs. −0.35kg) and median total cholesterol (−6.4 vs. −4.4mg/dL); no endpoint change was observed in median triglycerides (0.0 vs. 0.0mg/dL). There were no clinically significant changes in other laboratory or ECG parameters. Improvement was observed on an MMRM analysis of the PANSS total score for lurasidone and ziprasidone at Week 1 (−4.1 vs. −1.6; P=0.020), Week 2, (−6.1 vs. −3.6; P=0.074), and Week 3 (−6.3 vs. −4.5; P=0.229). Conclusion In this double-blind, fixed-dose comparison of lurasidone 120mg and ziprasidone 160mg, treatment with lurasidone was well-tolerated and safe, and was not associated with clinically significant changes from baseline in weight, metabolic parameters, or QTc interval. Study limitations include the relatively short trial duration and lack of placebo control.