Serotonin (5-HT3) receptor antagonists are the foundation of standard antiemetic care for cancer patients receiving emetogenic chemotherapy. To enhance the efficacy of these supportive care agents, dexamethasone is routinely admixed with the 5-HT3 receptor antagonist, which is administered by intravenous infusion before chemotherapy begins. This phase II study evaluated the safety and efficacy of intravenous palonosetron admixed with dexamethasone to prevent chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy. Cancer patients received palonosetron 0.25 mg plus dexamethasone 8 mg admixed in 50 mL of infusion solution before receiving at least one qualifying chemotherapeutic agent (cyclophosphamide < or = 1,500 mg/m2, doxorubicin > or = 20 mg/m2, carboplatin, or oxaliplatin). Patients used diaries to record nausea and emesis experienced and rescue medications used. Of 32 participants, 27 (84%) had a complete response (no emesis and no rescue medication) during the acute (0-24 hours) interval posttherapy, 19 (59%) had a complete response during the delayed (> 24-120 hours) posttherapeutic interval, and 19 (59%) had a complete response during the overall (0-120 hours) posttreatment interval. A total of 23 patients (72%) had no emetic episodes, 16 (50%) had no nausea, and 21 (66%) used no rescue medication throughout the overall 5-day interval. The combination was well tolerated. Palonosetron plus dexamethasone given as a pretreatment infusion is effective and safe in preventing acute and delayed CINV in patients receiving moderately emetogenic chemotherapy.