The exact incidence of postoperative nausea and vomiting (PONV) in patients on steroids undergoing neurosurgical procedures is not known. This prospective randomized double-blind study was planned to know the efficacy of prophylactic ondansetron in the prevention of PONV in patients on steroids as compared with placebo. Seventy adult patients of either sex who had received preoperative steroids (dexamethasone) for at least 24 hours and were scheduled to undergo craniotomy for supratentorial tumors were included. Patients were randomly allocated using a randomization chart to 1 of the 2 groups to receive either ondansetron 4 mg (group O) or 0.9% saline (group S) intravenously at the time of dural closure. Numeric Rating Scale score for nausea and pain intensity was recorded preoperatively and till 24 hours postoperatively. The 6-hour postoperative nausea score was significantly lower in group O [median, 0; interquartile range (IQR), 0 to 20] than in group S (median, 20; IQR, 0 to 20) (P<0.05). The incidence of vomiting was lower in group O (23%) than in group S (46%) (P<0.05). The total number of emetic episodes, the number of doses of rescue antiemetics given in the first 6 postoperative hours, and the total number of rescue antiemetics given were significantly lower in group O than in group S (P<0.05). Intravenous administration of 4 mg of ondansetron at the time of dural closure was effective in reducing the incidence of PONV and the rescue antiemetics requirement in patients on preoperative steroids undergoing craniotomy for supratentorial tumors.