OBJECTIVES:  Currently, several branded and generic serotonoin-3 receptor antagonists (5HTRAs) are indicated for chemotherapy induced nausea and vomiting (CINV). While these medications differ in efficacy and acquisition cost, palonosetron is a second generation 5HTRA commonly recommended by treatment guidelines (e.g., NCCN, MASCC, ASCO). Using a decision analytic model, this study examined the financial impact of a 5% increase in the utilization of palonosetron vs. a generic 5HTRA (ondansetron) in cancer treated with a highly (HEC) or moderately emetogenetic chemotherapy (MEC). The results illustrate the costs to manage CINV from a payer perspective. METHODS:  The model generated outputs for a hypothetical one-million member healthplan. The eligible population was determined from national rates of cancer and chemotherapy. Antiemetic-specific rates of CINV were based on retrospective analyses defining CINV by ICD9 codes or use of rescue antiemetics. Other inputs included current 5HTRA market share, medication acquisition costs, and per-patient costs to treat CINV. Model outputs predicted pharmacy and medical costs in the base year and following the 5% utilization increase. RESULTS:  The model predicted a population of 968 patients, 282 (14.1%) treated with HEC and 686 (34.3%) with MEC. Increasing the utilization of palonosetron by 5% (59% to 64% in HEC, 51% to 56% in MEC) resulted in an increase in pharmacy acquisition costs from $1.85 million to $1.92 million. CINV treatment costs, however, would decrease from $8.66 to $8.41 million. Overall, net costs for the MCO decreased by $1.77K, or $0.02 PMPM. CONCLUSIONS:  As expected, this model predicted an increase in pharmacy costs from the increased utilization of palonosetron relative to generic ondansetron. However, because the rate of CINV control associated with palonosetron was lower than with ondansetron, CINV treatment costs decreased. Increasing the utilization of palonosetron in MEC and HEC, then, may result in an overall net savings to a health plan.