OBJECTIVES: NCCN guidelines recommend a serotonin-3 receptor antagonist (5-HT-RA), a substance P/neurokinin 1 (NK1) receptor antagonist, and dexamethasone for patients undergoing highly emetogenic chemotherapy (HEC) for the prevention of chemotherapy-induced nausea and vomiting (CINV). This same combination is also recommended in patients using moderately emetogenic chemotherapy (MEC) at higher risk for CINV. This study estimated the budget impact of adopting netupitant/palonosetron (NEPA), an oral fixed-dose combination of a 5-HT-RA and an NK1 for antiemetic prophylaxis, from a U.S. health plan perspective. METHODS: A decision analytic model compared treatment costs before and after adoption of NEPA in a hypothetical ten-million member health plan over a 3-year horizon. Estimates of plan cancer rates and utilization of HEC and MEC therapies were derived from epidemiological and market data. Treatment costs were computed using standard prescribing dosages, U.S. drug cost listings and simple reimbursement and dispensing assumptions. Uptake of NEPA was calculated at 5% a year for 3 years, and competing antiemetic therapies were reduced proportionately based on initial share assumptions. RESULTS: A total of 54,000 patients with cancer were identified in the model scenario.  Of these, 9,882 (18.3%) would receive HEC and 3,949 (7.3%) would receive MEC requiring combination therapy, for a total of 13,830 eligible for NEPA. Cost of CINV prevention prior to the adoption of NEPA was estimated at $40.96 million. Following adoption of NEPA, cumulative costs were reduced by nearly $652K by the end of year 3. Calculations using PMPM estimates showed cumulative savings of $0.002 in year 1, $0.004 in year 2, and $0.005 in year 3. CONCLUSIONS: Results of the model indicate that adoption of NEPA for the prevention of CINV may have a relatively neutral impact on a U.S. health plan budget. Additionally, these estimates do not include savings from a potential reduction in the overall rate of CINV.