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Abstract Background Amisulpride was introduced into China in 2010 as a second-generation atypical antipsychotic, while olanzapine has been on the market since 1999 as one of the leading treatments for schizophrenia in China. Since more Chinese patients are gaining access to amisulpride, the study aims to compare the efficacy, safety, and costs between amisulpride and olanzapine for schizophrenia treatment in China. Methods PubMed, Embase, the Cochrane library, China National Knowledge Infrastructure (CNKI) and WanFang database were systematically searched for randomized controlled trials (RCTs) up to July 2018. The Cochrane Risk of Bias tool was utilized to assess the quality of included studies. A meta-analysis was performed to compare the efficacy and safety of amisulpride and olanzapine, followed by a cost-minimization analysis using local drug and medical costs reported in China. Results Twenty RCTs with 2000 patients were included in the systematic review. There were no significant differences between amisulpride and olanzapine on efficacy measures based on scores from the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Brief Psychiatric Rating Scale and the Clinical Global Impressions-Severity or Improvement. For safety outcomes, amisulpride was associated with lower fasting blood glucose and less abnormal liver functions as well as significantly lower risks of weight gain, constipation, and somnolence; olanzapine was associated with significantly lower risks of insomnia and lactation/amenorrhea/sexual hormone disorder. No significant differences were found in risks of extrapyramidal symptoms (EPS), tremor, akathisia, abnormal corrected QT interval. Cost-minimization analysis showed that amisulpride was likely to be a cost-saving alternative in China, with potential savings of 1358 Chinese Yuan (CNY) per patient for a three-month schizophrenia treatment compared with olanzapine. Conclusion As the first meta-analysis and cost-minimization analysis comparing the efficacy, safety and cost of amisulpride and olanzapine within a Chinese setting, the study suggests that amisulpride may be an effective, well-tolerated, and cost-saving antipsychotic drug alternative in China.