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In this randomized, double-blind study, we evaluated whether small-dose granisetron (0.1 mg) plus dexamethasone 8 mg (G+D) was as effective as ondansetron 4 mg plus dexamethasone 8 mg (O+D) for preventing vomiting during the 0 to 2 h after tracheal extubation in patients undergoing abdominal hysterectomy requiring general anesthesia. Dexamethasone (D) was administered at induction of anesthesia, and granisetron (G) or ondansetron (O) was given approximately 15 min before tracheal extubation. Data on postoperative nausea and vomiting were collected at 0, 2, 6, and 24 h. For the primary efficacy endpoint, most patients in each group had no vomiting in the 0- to 2-h interval (82/87 [94%] for G+D versus 86/89 [97%] for O+D). Effectiveness of G+D was demonstrated versus O+D. Treatment groups were similar with regard to moderate or severe nausea, complete response, rescue medication use, and total control over 24 h. A descriptive assessment of adverse events showed that both combinations were well tolerated with infrequent and similar incidences of adverse events. The combination of small-dose G administered just before tracheal extubation plus D given at induction of anesthesia is an effective alternative to O+D in preventing vomiting during the 0- to 2-h interval after tracheal extubation.