BACKGROUND AND OBJECTIVES: Postoperative nausea and vomiting (PONV) notably affects up to 30% of surgical patients, resulting in elevated medical service costs, dehydration, discomfort, and delayed recovery. Although standard antiemetic medications are effective, but they may not completely prevent PONV due to complicated underlying pathophysiology involving various neurotransmitter systems. Therefore, this systematic review and meta-analysis evaluates the efficacy and safety of olanzapine, an atypical antipsychotic with wide-spectrum receptor antagonism, in PONV reduction. METHODS: A comprehensive literature search was conducted to retrieve randomized controlled trials (RCTs) comparing prophylactic olanzapine to other traditional antiemetics or placebo in multiple electronic databases, including PubMed, Scopus, Cochrane Library, and Web of Science. However, the main outcome was the incidence rate of PONV within 24 hours postsurgical operations. Furthermore, risk differences (RD) and relative risks (RR) were calculated on Review Manager (RevMan), and trial sequential analysis (TSA) was established to precisely assess the evidence reliability of olanzapine. RESULTS: Five RCTs with 793 patients were eligible for our inclusion criteria. Olanzapine potentially decreased PONV risk (RR = 0.67
95% CI, 0.56, 0.80) and absolute risk reduction by 15% (RD = -0.15
95% CI, -0.24, -0.06). Furthermore, subgroup analysis by dose revealed that the 10 mg dose of olanzapine had a strong effect in lowering PONV. However, only the 5 mg dose showed a statistically significant reduction in the use of rescue antiemetics (RR = 0.28
95% CI, 0.10, 0.84). Moreover, TSA demonstrated and confirmed notable evidence supporting the efficacy of olanzapine. CONCLUSION: Olanzapine potentially decreases PONV incidence rates, particularly when combined with traditional antiemetics, indicating its pivotal role in PONV prevention. There is a pressing need for further research to optimize dosing and assess its efficacy among different surgical populations and procedures.