©2016 Frontline Medical Communications. Background: Concurrent chemotherapy radiation therapy may result in significant nausea and vomiting. There have been few studies reporting effective interventions for preventing treatment-related nausea and vomiting. Objective: To compare olanzapine with fosaprepitant for the prevention of nausea and vomiting in patients receiving concurrent highly emetogenic chemotherapy (HEC) and radiotherapy for locally advanced head and neck or esophageal cancer. Methods: 120 chemotherapy and radiotherapy naïve patients with head and neck cancer who were receiving concurrent local radiation and cisplatin were randomized to receive either olanzapine or fosaprepitant in combination with palonosetron and dexamethasone for the prevention of chemotherapy- and radiation-induced nausea and vomiting. The olanzapine, palonosetron, dexamethasone (OPD) regimen was 10 mg oral olanzapine, 0.25 mg IV palonosetron, and 20 mg IV dexamethasone before chemotherapy on day 1, and 10 mg/day of oral olanzapine before chemotherapy on days 2-4. The fosaprepitant, palonosetron, dexamethasone (FPD) regimen was 150 mg IV fosaprepitant, 0.25 mg IV palonosetron, and 12 mg IV dexamethasone before chemotherapy on day 1, and 4 mg dexamethasone PO BID, before chemotherapy days 2 and 3. Results: 101 of the 120 patients were evaluable. In 51 patients who received the OPD regimen, the complete response (CR; no emesis, no rescue medication) rate was 88% for the acute period (24 h after chemotherapy), 76% for the delayed period (days 2-5), and 76% for the overall period (0-120 h). In 50 patients who received the FPD regimen, the CR was 84% acute, 74% delayed, and 74% overall (P > .01 for all periods). Patients with no nausea (0, on a scale 0-10, visual analogue scale) were: OPD: 86% acute, 71% delayed, 71% overall; FPD: 78% acute, 40% delayed, 40% overall (P > .01 for acute; P < .01 for delayed and overall) There were no grade 3 or 4 toxicities. Conclusions: CR was similar for OPD and FPD; nausea in the delayed and overall periods was signifcantly improved with OPD compared with FPD (P < .01).