OBJECTIVES: To examine the impact of palonosetron vs. other 5-HT3 RAs on incidence of delayed CINV at cycle 1 based on presence of certain risk factors (age <50 years, female gender, prior CINV, anxiety, no or minimal alcohol use, history of motion sickness, and emetogenicity of chemotherapy). METHODS: A retrospective claims analysis was conducted using OptumInsight database from December 1, 2005 to June 30, 2011. Continuously enrolled cancer patients >18 years of age initiated on their first chemotherapy (index date) were included. Patients with a previous cancer diagnosis in the pre-index period or receiving multi-day chemotherapy were excluded. The study population was examined for differences in CINV rates by each 5-HT3 RA stratified by number of risk factors (female gender, age <50, previous anxiety, vomiting pre-index, and highly emetogenic chemotherapy. CINV was identified using ICD9CM codes for nausea, vomiting, or related events, and rescue medication use within 5 days after chemotherapy. RESULTS: Final analysis included 26,974 patients. Overall the percentage of patients experiencing CINV increased as the number of risk factors increased – 13.5%, 14.9%, 15.6%, and 18.4% for 0, 1, 2, and 3 or more risk factors, respectively. High-risk patients (3 or more risk factors) receiving palonosetron had less CINV events compared to ondansetron, granisetron, and dolasetron. Odds Ratios (OR) 95%CI vs. palonosetron were 1.523 (1.231, 1.883), 1.426 (1.146, 1.773), and 1.683 (1.271, 2.229), respectively. CONCLUSIONS: The probability of a CINV event increased with the accumulation of identified risk factors. Palonosetron demonstrated a statistically significant OR vs. all other 5-HT3 RA in patients at the highest risk of developing a CINV event.