Background: Currently, the NK-1 receptor antagonist (NK-1 RA) aprepitant combined with a 5-HT₃ receptor antagonist (5-HT₃ RA) and dexamethasone (DEX) constitutes the antiemetic standard of care with highly emetogenic chemotherapy (HEC) and with the moderately emetogenic chemotherapy (MEC) agents cyclophosphamide and anthracyclines (AC) when used together. The role of the NK-1 RA’s with MEC other than AC is less clear. Casopitant (GW679769) is an NK-1 RA with demonstrated efficacy when added to ondansetron and DEX in both the HEC and AC-MEC settings. This study was conducted to determine if the addition of a single dose of casopitant to ondansetron and DEX would improve the control of CINV following oxaliplatin-based MEC compared to ondansetron and DEX alone. Methods: Patients (pts) with colorectal cancer undergoing their first cycle of oxaliplatin (85 mg/m²–130 mg/m²) in combination with 5-flourouracil/leucovorin or capecitabine were randomized to receive casopitant (C) 90 mg or placebo (PL) intravenously (IV) and DEX 8 mg IV both on day 1 prior to chemotherapy, added to ondansetron 8 mg bid orally (PO) on days 1-3. The primary endpoint was the percentage of pts achieving complete response (CR; no vomiting/retching or use of rescue medication in the 120 hours after the start of chemotherapy. Results: Subjects – 710, median age - 61.3, females 44%, performance status 0-1 – 99%. Overall CR: C – 86%, PL – 85% (p =0.7273); acute (< 24 hours) CR: C – 97%, PL 96%; delayed (24-120 hours) CR: C – 86%, PL 85%. No significant differences in secondary endpoints of no emesis or no nausea were noted. Conclusions: Addition of a single 90 mg IV dose of casopitant did not improve the control of CINV with oxaliplatin-based MEC. In this setting, excellent control of CINV was achieved with the combination of a 5-HT₃ RA and DEX alone. Unlike with cisplatin and AC chemotherapy, the emetogenic challenge posed by oxaliplatin-based chemotherapy may not be sufficient to warrant the use of an NK-1 RA.