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Background: Subarachnoid (SA) morphine, highly effective for the management of pain after a cesarean delivery, is associated with a significant incidence of pruritus in up to 80% of patients. No previous study has compared the effectiveness of ondansetron (5-HT3 antagonist) vs. diphenhydramine (H1 receptor blocker) for the treatment of this side effect. Methods: In this randomized, double-blind study, 113 patients with a pruritus score 3 or 4 (1=absent; 2=mild, no treatment required; 3=moderate pruritus, treatment required; and 4=severe pruritus) after SA morphine 0.2 mg were assigned to group ondansetron, which received 4 mg intravenously (i.v.) ondansetron, and group diphenhydramine, which received 25 mg i.v. diphenhydramine. Patients who continued to have pruritus ≥3 30 min after the study drug were considered treatment failures and were treated with naloxone 0.04 mg i.v. repeatedly, as well as patients who relapsed. Pain scores, nausea, vomiting, and sedation were determined before and 30 min after the study drugs were administered. Patients were followed up for 24 h. Results: The success rate was comparable between the two groups [40/57 (70%) and 38/56 (70%), P=0.79, in group ondansetron and group diphenhydramine, respectively]. Among the successfully treated patients, the recurrence rates of moderate to severe pruritus were 11/40 (28%) in group ondansetron and 13/38 (35%) in group diphenhydramine, P=0.52. The side effect profile was similar between the two groups. Conclusion: Ondansetron is as effective as diphenhydramine in relieving pruritus caused by SA morphine in patients undergoing a cesarean delivery. However, up to 50% of patients required naloxone either for primary failure or for recurrence.