OBJECTIVES: To assess the rate of uncontrolled chemotherapy induced nausea and vomiting (CINV) associated with palonosetron initiation versus other 5-hydroxy tryptamine3-receptor antagonists (5-HT3-RAs) among Medicare patients with cancer on chemotherapy (CT) treatment in a hospital outpatient setting. METHODS: Medicare patients with a cancer diagnosis initiating CT and anti-emetic prophylaxis with palonosetron (Group 1) and other 5-HT3-RAs (Group 2) for the first time (index date) between April 1, 2007 – March 31, 2009 were identified from the Premier Perspective database. Inclusion criteria were no evidence of nausea and vomiting, CT, and anti-emetic medication in the 6-month pre-index date period and 36-consecutive months of data submission. A negative binomial distribution generalized linear multivariate regression model estimating the rate of CINV events on CT emetogenicity and cycle matched groups in the follow-up period (first of eight CT cycles or six months post-index date) was developed after adjusting for several demographic and clinical variables. RESULTS: Of 4799 identified patients, 962 initiated palonosetron (Group 1; 20.1%). Group 1 patients were significantly younger [70.4 (SD: 9.3) versus 71.6 (9.0) years; p<0.0001], comprised more females [52.9% versus 48.6%; p<0.0001], less African-Americans [8.7% vs. 11.3%] and more Hispanic patients [6.3% versus 2.5%]; all p<0.0001, more highly and moderately emetogenic CT [33.6% versus 20.7% and ; 47.3% versus 40.3%, respectively; p<0.0001], and more lung and breast [30.9% vs. 24.9% and 12.3% vs. 9.6%, respectively; p<0.0001]. In the follow-up period, the regression model predicted a 11.8% decrease in the CINV events per CT cycle for Group 1 patients versus Group 2 patients; p<0.05. CONCLUSIONS: In this retrospective hospital outpatient study, after matching for CT emetogenicity and cycle and adjusting for other potential confounders, Medicare patients with cancer initiated on palonosetron were more likely to experience a significantly lower rate of CINV events per CT cycle versus those initiating other 5-HT3-RAs.