Dimenhydrinate is an inexpensive antihistaminic drug, that is frequently used as an anti-emetic during anaesthesia. The popularity of the drug is contrasted by the lack of modern studies concerning its efficacy in reducing the incidence of post-operative nausea and vomiting. Thus, dimenhydrinate was compared with placebo in this prospective, randomized, double-blind study. One hundred and thirty-three female in-patients were studied. They were stratified according to the type of surgery (laparoscopic cholecystectomy, thyroid resection or knee arthroscopy) to ensure an homogenous distribution in both groups. General anaesthesia was induced with etomidate, fentanyl, vecuronium and maintained with enflurane in N2O/O2. Neuromuscular block was reversed with pyridostigmine/atropine. Patients in the dimenhydrinate group (n=67) received 62 mg dimenhydrinate intravenously after induction of anaesthesia. Placebo patients (n=66) received saline. Administration of dimenhydrinate (and placebo) was repeated three times during the 48-h study to mitigate the short half-life of the drug. Post-operative analgesia and anti-emetic rescue medication was standardized. Episodes of vomiting, retching and the need for additional anti-emetics were recorded. Nausea was assessed using a 10-cm visual analogue scale. Post-operative nausea and vomiting was rated as ‘none’, ‘mild’, ‘moderate’ and ‘severe’ using a fixed scoring algorithm. There were no differences between the two groups with regard to biometric data, type of surgery and distribution of risk factors for developing post-operative nausea and vomiting. In the dimenhydrinate group, more patients remained completely free from post-operative nausea and vomiting compared with placebo (dimenhydrinate: 38.8%; placebo:15.1%; P=0.004). The incidence of severe post-operative nausea and vomiting was also reduced from 39.4% to 14.9%. No relevant side effects were observed. Intra-operative dimenhydrinate, followed by three further administrations after surgery, reduces the incidence and the severity of post-operative nausea and vomiting without side effects. However, there still remained an unacceptable high number of patients who were not prevented completely from experiencing post-operative nausea and vomiting.