Objective: There is growing awareness of the increased prevalence of metabolic abnormalities in patients with schizophrenia. Thus, the safety and tolerability of atypical antipsychotic (AAP) medications are important considerations in the choice of agents to treat severe mental illness. In a systematic review of the published literature on AAPs, we explored differences in metabolic effects between ziprasidone and olanzapine. Methods: We identified 300 published studies of AAPs in schizophrenia, including head-to-head, placebo-controlled trials and observational studies. A meta-analysis was performed on the safety and tolerability of ziprasidone and olanzapine in areas with sufficient data (i.e., at least three studies for each outcome). Studies were included in meta-analyses if they provided sample size, mean change, and measure of variance, or if they reported data to allow for imputation of these values. We considered changes in total cholesterol, triglycerides, body weight, QTc interval, and discontinuation due to adverse events. Results: Of 13 publications reporting a head-to-head comparison of ziprasidone vs. olanzapine, four provided data useful for pooled analyses. When compared to ziprasidone, olanzapine use was associated with increased total cholesterol (mean difference 20.0 mg/dL [95% CI 9.8 mg/dL, 30.2 mg/dL]), triglycerides (mean difference 66.6 mg/dL [95% CI 43.6 mg/dL, 89.7 mg/dL]), and body weight (mean difference 4.97 kg [95% CI 4.1 kg, 5.8 kg]). Mean daily doses ranged from 112.8 mg to 135.2 mg (ziprasidone) and from 12.6 mg to 20.5 mg (olanzapine). Mean changes in the QTc interval and rates of discontinuation due to adverse events were similar for ziprasidone vs. olanzapine (studies not pooled). Limitations of the study included heterogeneity across the head-to-head trials: study durations ranged from 6 to 18 months. Conclusion: These results point to clinically important and statistically significant advantages for ziprasidone in metabolic safety compared with olanzapine. Ziprasidone's effect on the QTc interval and tolerability are similar to olanzapine.