Purpose: Olanzapine-containing regimens have been reported to be effective in preventing CINV following highly emetogenic chemotherapy (HEC), but it is unsure whether it is cost-effective. There has been no cost-effectiveness analysis conducted for olanzapine using costs from the USA. The aim of this study is to determine whether olanzapine-containing antiemetic regimens are cost-effective in patients receiving HEC. Methods: A decision tree model was constructed to evaluate the cost and health outcomes associated with olanzapine-containing antiemetic regimens and otherwise-identical regimens. One-way sensitivity analyses were conducted to individually investigate the effect of (i) lower complete response (CR) rates of olanzapine, closer to non-olanzapine-containing regimens; (ii) higher FLIE scores for patients who achieved no/incomplete response, closer to FLIE scores of patients achieving a complete response; (iii) differing costs of olanzapine to reflect different costs per hospitals, globally, due to different insurance systems and drug costs; and (iv) varying costs for uncontrolled CINV, to account for varying durations of chemotherapy and accompanying uncontrolled CINV. Results: Olanzapine regimens have an expected cost of $325.24, compared with $551.23 for non-olanzapine regimens. Meanwhile, olanzapine regimens have an expected utility/index of 0.89, relative to 0.87 for non-olanzapine regimens. Olanzapine-containing regimens dominate non-olanzapine-containing regimens even if CR of olanzapine-containing regimens fall to 0.63. Only when CR is between 0.60 and 0.62 is olanzapine both more effective and more costly. Conclusion: Olanzapine-containing regimens are both cheaper and more effective in the prophylaxis of CINV in HEC patients, compared with non-olanzapine-containing regimens. Future CINV trial resources should be allocated to understand newer antiemetics and compare them to olanzapine-containing regimens as the control arm. Further analysis should use nationally representative data to examine medication costs by payer type.