OBJECTIVES: 5-hydroxytryptamine3 receptor antagonists (5-HT3 RAs) are used for prophylaxis of chemotherapy-induced nausea and vomiting (CINV). This study compared the risk of severe CINV associated with hospitalization or emergency room admission among patients with lymphoma initiated and maintained on palonosetron versus the other 5-HT3 RAs (granisetron, ondansetron, and dolasetron).  METHODS: Adult patients diagnosed with lymphoma and treated with cyclophosphamide were selected from PharMetrics claims data (2005-2009). Other inclusion criteria were continuous patient enrollment for at least ≥6 months before the initial diagnosis and receipt of 5-HT3 RA for CINV prevention on the day of cyclophosphamide treatment (index date). CINV was identified by ICD-9-CM claims for nausea, vomiting, and/or dehydration. Risk of CINV during the follow-up period of 6 months from index date was assessed using multiple regression models, controlling for age, gender, Charlson Comorbidity Index (CCI), and total dose of cyclophosphamide.  RESULTS: A total of 2609 patients were studied. Palonosetron patients (n=979; 37.5%) were older than the other 5-HT3 RAs (62.1 ± 13.6 vs. 59.0 ± 14.1 years, p<0.0001), with similar CCI and gender. During follow-up, palonosetron patients received more cyclophosphamide dose in significantly fewer CT days (+586 mg; p=0.0005 and -0.73 days, both p<0.0001), and had fewer patients experiencing unadjusted severe CINV (7.3% vs. 10.4%, p=0.007) as compared to the other 5-HT3 RA patients. Multiple regressions found that palonosetron group (versus the other 5-HT3 RA group) experienced fewer CINV claims (0.47 less; p=0.0253), fewer CINV days (48% less; p=0.0006), and a 34% lower severe CINV risk (Odds Ratio=0.66; p=0.006). CONCLUSIONS: Patients in palonosetron group received higher CT dose within fewer CT days and experienced significantly lower risk for potentially costly CINV events than patients on other 5-HT3-RA-based antiemetic prophylaxis. Further studies on the clinical and economic impact of the choice of 5-HT3-RA for CINV prophylaxis in patients with lymphoma are needed.