We studied the effect of combining prophylactic ondansetron (4 mg intravenously [IV]) to desflurane-based anesthesia in 90 ASA grade I or 11 women undergoing outpatient gynecological laparoscopy. Recovery after anesthesia, with special focus on postoperative nausea and vomiting (PONV), was assessed. Control groups received a similar desflurane anesthetic (placebo) or a propofol-infusion-based (active control) anesthetic. The study design was randomized, controlled, and double-blind (regarding ondansetron) and single-blind (regarding the anesthetic technique). Early recovery (eye opening, orientation, following commands, sitting) was similar in the three groups. However, overall home readiness (toleration of oral fluids, walking, pain tolerable by oral analgesics, no or only mild nausea) was achieved faster in the desflurane group receiving ondansetron (109 [21-937] min, P < 0.01) and in the propofol group (110 [33-642] min, P < 0.001) when compared to the desflurane only group (372 [45-723] min) (median [range]). The total incidence of PONV in the desflurane-only group was 80% (P < 0.01), compared to 40% and 20% in the desflurane group receiving ondansetron and the propofol group, respectively. The postoperative antiemetic requirements were consistently and significantly (P < 0.01) higher in the desflurane-only group compared to the other two groups. Postoperative sedation, analgesic requirements, and psychomotor recovery (assessed by the Maddox Wing and the Digit Symbol Substitution Tests) were similar in the three groups. Our results suggest that in order to achieve a propofol-like recovery profile in patients with a high likelihood of PONV, desflurane should be combined with a potent antiemetic (e.g., ondansetron).