EnAbstract Background This study aimed to evaluate the efficacy of palonosetron, the 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, in preventing postoperative nausea and vomiting (PONV) after middle ear surgery. Patients and methods Sixty-two ASA I and II patients who had undergone middle ear surgery under general anesthesia were included in a double-blind, placebo-controlled study and were enrolled into two groups: palonosetron group (P) and placebo control group (C). Patients were administered 0.075 mg of palonosetron or isotonic saline, respectively. The incidence of PONV and requirement of rescue antiemetics were assessed. The severity of nausea was evaluated according to the visual analogue scale. Patients who had not experienced any attack of vomiting or received rescue drug were considered to have a complete response. Results The incidence of PONV was significantly lower in group P than that in the control group C during (0–4 h) P-value less than 0.001 and (4–24 h) 0.05 periods, and the incidence of complete response was 83.7% in group P and 6.5% in group C (P<0.001). Conclusion Palonosetron could provide effective prophylactic antiemetic control to prevent PONV after middle ear surgery under general anesthesia.