The objective of this multicenter, phase II, open-label study was to evaluate the safety and efficacy of the newest 5-hydroxytryptamine3 (5-HT3) receptor antagonist, palonosetron, plus dexamethasone and aprepitant in preventing nausea and vomiting in patients receiving moderately emetogenic chemotherapy. Eligible patients received a single intravenous dose of palonosetron (0.25 mg on day 1 of chemotherapy), along with 3 daily oral doses of aprepitant (125 mg on day 1,80 mg on days 2 and 3) and dexamethasone (12 mg on day 1,8 mg on days 2 and 3). Efficacy and safety data were obtained from patient diaries and adverse event reporting. Fifty-eight patients were evaluable; 47% were women with breast cancer and 52% received cyclophosphamide-based chemotherapy. The proportion of patients with complete response (no emesis and no rescue medication) was 88% during the acute (0-24 hours) interval, 78% during the delayed (> 24-120 hours) interval, and 78% during the overall (0-120 hours post chemotherapy) interval. More than 90% of patients during all time intervals had no emetic episodes, and between 57% and 71% of patients reported no nausea during each of the 5 days post chemotherapy. Treatment was well tolerated, with no unexpected adverse events. These data demonstrate that palonosetron in combination with dexamethasone and aprepitant is safe and highly effective in preventing chemotherapy-induced nausea and vomiting in the days following administration of moderately emetogenic chemotherapy.