Purpose Olanzapine has been shown to have an additive effect on the three-drug antiemetic therapy, consisting of aprepitant, palonosetron, and dexamethasone, in a highly emetogenic cisplatin-containing chemotherapy. Although olanzapine may be more economical than aprepitant or palonosetron, an adequate cost-efficacy analysis has not been conducted. We conducted a cost-utility analysis to evaluate the cost-effectiveness of olanzapine in four-drug antiemetic therapy among Japanese patients.Methods We simulated model patients treated with highly emetogenic cisplatin-containing chemotherapy and developed a decision-analytical model of patients receiving triple antiemetic therapy with or without olanzapine. The cost, probabilities, and incremental cost-effectiveness ratio (ICER) of each treatment were calculated from the perspective of the Japanese healthcare payer. The threshold ICER was set at 45,867 United States dollars (USD) (5 million Japanese yen) per quality-adjusted life-year (QALY). The probabilities, utility value, and other costs were obtained from published sources. The robustness of this model was validated by one-way sensitivity analysis and probabilistic sensitivity analysis.Results The calculated ICER was 5,156 USD/QALY, which was below the threshold. Under the set conditions, the probabilistic sensitivity analysis revealed a 100% probability that olanzapine was cost-effective. Based on the one-way sensitivity analysis, reducing the cost of olanzapine below 10.78 USD placed the ICER below the threshold. Conclusion Olanzapine was cost-effective in the four-drug antiemetic therapy for Japanese patients treated with highly emetogenic cisplatin-containing chemotherapy