OBJECTIVES: Palonosetron, dolasetron, granisetron, and ondansetron [5-HT3 receptor antagonists (5-HT3-RAs)] are indicated to prevent chemotherapy-induced nausea and vomiting (CINV). Despite alternate CINV prophylaxis options, nausea still remains an undesirable side effect that is difficult to measure. This study evaluates the likelihood of uncontrolled chemotherapy-induced nausea following antiemetic prophylaxis with palonosetron + aprepitant + dexamethasone (group 1) versus any of the other 5-HT3-RAs + aprepitant + dexamethasone (group 2) among single-day HEC cycles in cancer diagnosed patients. METHODS: Single-day HEC cycles (a gap of at least 5 days between 2 administrations) among patients with a cancer diagnosis and initiating antiemetic prophylaxis with group 1 versus group 2 between January 1, 2006 to June 30, 2010 were identified from the IMS LifeLink claims database. Uncontrolled chemotherapy-induced nausea events were defined as ICD-9-CM codes for nausea, CPT codes for hydration, rescue medications, and/or use of antiemetic therapy from days 2-5 following HEC administration. Risk for an uncontrolled chemotherapy-induced nausea event was analyzed at cycle level using a logistic multivariate regression model. RESULTS: A total of 8018 group 1 and 1926 group 2 cycles (3,574 and 978 patients, respectively) were analyzed. Groups 1 and 2 were similar in age [mean (sd): 52.8 (11.7) vs. 52.9 (11.6) years; p=0.861], Charlson comorbidity score [6.2 (3.1) vs. 6.2 (3.0); p=0.978], female (77.2% vs. 78.2%; p=0.4857), and cancer type distribution.  Versus group 2, group 1 cycles had a significantly lower unadjusted risk of an uncontrolled chemotherapy-induced nausea event (17.1% vs. 20.0%; p=0.0023), while the multivariate regression analysis predicted a 12% lower risk for group 1 cycles [Odds Ratio: 0.88 (95% CI: 0.77 – 0.995); p=0.0403].  CONCLUSIONS: In this retrospective claims data analysis, patients with cancer receiving single-day HEC cycles and palonosetron based triple drug prophylaxis for CINV had a lower risk for an uncontrolled chemotherapy-induced nausea event versus older 5-HT3-RAs.