OBJECTIVES: To assess the rate of chemotherapy induced nausea and vomiting (CINV) associated with palonosetron (a 5-hydroxy tryptamine3-receptor antagonist [5-HT3-RA]) initiation versus other 5-HT3-RAs among patients with cancer on highly [HEC] or moderately emetogenic chemotherapy (CT) [MEC] treatment in a hospital outpatient setting. METHODS: Patients with a cancer diagnosis initiating HEC or MEC and anti-emetic prophylaxis with palonosetron (Group 1) or other 5-HT3-RAs (Group 2) for the first time (index date) between 4/1/2007 – 3/31/2009 were identified from the Premier Perspective comparative database. Inclusion criteria were patients aged ≥ 18 years with no evidence of nausea and vomiting or use of HEC/MEC or anti-emetic medication in the 6-month pre-index date period, and with 36-consecutive months of hospital data. Follow-up time was first of eight CT cycles (a cycle was the unit of analysis) or six months post-index date. A negative binomial distribution generalized linear multivariate regression model estimating the CINV event rate on CT matched groups in the follow-up period was developed after controlling for demographic and clinical variables. RESULTS: Of 6418 identified patients, 1522 (23.7%) initiated palonosetron. Group 1 patients comprised of less African Americans (8.7% vs. 14.2%) and more Hispanics (5.7% vs. 4.5%); p<0.0001, more patients on HEC [50.5% vs. 41.5%; p<0.0001], and more non-colon gastrointestinal (10.3% vs. 6.3%) and breast cancer patients (19.5% vs. 16.8%); p<0.0001. In the follow-up period, the number of unadjusted CINV events between the matched groups was lower for Group 1 [6957 vs. 7784; p=0.054] patients. The regression model predicted a significant decrease (12.5%) in the CINV event rate per CT cycle for Group 1 patients versus Group 2 patients; p=0.0044. CONCLUSIONS: In this retrospective hospital outpatient study, patients with cancer treated with HEC/MEC and initiated on palonosetron were more likely to experience a significantly lower rate of CINV events versus those initiating other 5-HT3-RAs.