Post-operative nausea and vomiting is distressing for patients and can cause dissatisfaction and impaired well-being in the post-operative period. This study examined the question whether the reduced incidence of post-operative nausea and vomiting inevitably translates into improved clinical status and well-being. In this context high doses of droperidol were investigated. On the one hand, droperidol is known to be a powerful anti-emetic, but on the other hand there is concern about psychological effects, both in the pre- and the post-operative period. In this prospective randomized double-blinded study, droperidol (5–7.5 mg) was compared with midazolam (5–7.5 mg) used to supplement fentanyl-N2</O based anaesthesia, with respect to post-operative mood and well-being using a psychological questionnaire (Bf-S-test). Furthermore, the incidence of post-operative nausea and vomiting was recorded. Out of 160 patients undergoing thyroidectomy and laparoscopic cholecystectomy, data from 150 patients were analysed. The administration of droperidol significantly lowered the incidence of post-operative nausea and vomiting from 77.8% to 55.1% compared with midazolam (P=0.0059; χ2-test). Although post-operative nausea and vomiting is an independent risk factor for post-operative discomfort and bad mood, patients receiving droperidol showed impaired well-being 6 h after surgery. Well-being scores returned to pre-operative base-line values and did not differ between the two groups 24 and 48 h post-operatively. The reduced incidence of post-operative nausea and vomiting achieved with high dose droperidol does not equate with increased post-operative well-being. It is an important point at issue to decide whether smaller doses of droperidol that are commonly used for anti-emetic therapy are free of these side effects.