Background. Refractory postoperative nausea and vomiting (PONV) requiring repeated treatment with antiemetic drugs is a miserable experience for the patient that may substantially increase the cost of care. As risk stratification may aid in prophylaxis and treatment, we explored risk factors for severe PONV in patients enrolled in a large international, randomized controlled trial (the ENIGMA trial).Methods. Two thousand and fifty patients, aged >= 18 yr and undergoing surgery anticipated to exceed 2 h in duration, were recruited. Patients were randomized to nitrous oxide (N2O)-based or N2O-free anaesthesia. Choice of other anaesthetic, analgesic, and antiemetic drugs was left to the discretion of the anaesthetist. Anaesthetic depth was adjusted according to clinical judgement and, if available, bispectral index (BIS) monitoring. Severe PONV was defined as: (i) two or more episodes of expulsion of gastric contents at least 6 h apart; (ii) received at least three doses of antiemetic medication for treatment of PONV, within 24 h of surgery; or both. We used logistic regression, and classification and regression tree analysis, to define risk factors for severe PONV.Results. Three hundred and thirty-three (16.6%) patients experienced severe PONV. Age < 55 yr, female sex, abdominal surgery, N2O administration, absence of BIS monitoring, and longer duration of anaesthesia were predictors of severe PONV [area under receiver operating characteristic curve=0.70 (95% confidence interval: 0.67-0.73)].Conclusions. Severe PONV was common and risk factors for it were similar to those reported in other studies that included all patients reporting nausea, vomiting, or both.