Lung cancer is the leading cause of cancer-related death for both men and women worldwide, and lung cancer also has the highest morbidity and mortality rate among all cancers in China. Chemotherapy (CT) is the most effective and most widely used treatment for lung cancer. Nausea and vomiting are still among the most unpleasant side effects of chemotherapy, especially during highly emetogenic chemotherapy. The standard therapy for preventing chemotherapy-induced nausea and vomiting (CINV) is 5-hydroxytryptamine 3 (5-HT3) receptor antagonists. Palonosetron is a highly potent second-generation selective 5-HT3 receptor antagonist with stronger binding affinity for the 5-HT3 receptor. Palonosetron showed a high antiemetic activity in preclinical study and pivotal trails enrolling patients treated with moderately or high antiemetic activity drugs. Aim of the study was to verify the activity and safety of palonosetron in patients affected by non-small-cell lung carcinoma (NSCLC) and treated with chemotherapy. Patients with stage II-IV NSCLC and receiving chemotherapy entered into the trial. Informed written consent was required. Patients were randomized to received palonosetron or ondasetron. A single pretreatment dose of palonosetron 0.25 mg intravenous followed was administered. Nausea and vomiting were evaluated over 7-day period. Also the adverse effects were reported. Adverse events were evaluated according to the NCI-CTC criteria. Eighty-nine patients were enrolled into the study. The complete responses during the acute phase were 95.4 and 93.3%, respectively. The main side effects were headache 4.5%, constipation 15.7%, anxiety 2.3%. Palonosetron is a very active antiemetic drug for the prevention of nausea and vomiting in NSCLC patients received chemotherapy.