Introduction: In high-income countries, vomiting often impedes oral rehydration therapy, leading to intravenous rehydration fluid administration to children with acute gastroenteritis. Ondansetron administration reduces vomiting and intravenous fluid administration in this population. We evaluated whether ondansetron is similarly effective when employed in Pakistan. Methods: In this 2-hospital, double-blind, placebo-controlled, emergency department-based, randomized trial, we recruited children aged 0·5 to 5·0 years, without dehydration, who had diarrhea and 1 episode of vomiting within 4 hours of arrival. Patients were randomly assigned (1:1), via an internet-based randomization service, using a stratified, variable block randomization scheme, to receive a single dose of oral ondansetron or placebo. The primary endpoint was intravenous rehydration (administration of 20 ml/kg over 4 hours of an isotonic fluid) within 72 hours of randomization. All randomized children were analysed. Results: From July 3, 2014, to January 12, 2017, 626 children were randomized. Intravenous rehydration was provided to 10.8% (34/314) and 10.3% (27/312) of children administered placebo and ondansetron, respectively (OR: 0.946; 95% CI: 0.564, 1.587; P=0.834). A regression model fitted with treatment group and adjusted for antiemetic administration and vomiting frequency in the preceding 24 hours, yielded similar results; OR=0.952; 95% CI: 0.570, 1.589; P=0.850. There was no evidence of interaction between treatment group and age (P=0.974), 3 diarrheal stools in the preceding 24 hours (P=0.983) or 3 vomits in the preceding 24 hours (P=0.554). During the 4-hour study observation period, 24.0% (75/314) and 19.6% (61/312) of children in the placebo and ondansetron groups vomited, respectively; OR: 0.774; 95%CI: 0.528, 1.133; P=0.187. Conclusion: Ondansetron administration did not significantly reduce intravenous rehydration use, suggesting that in children without dehydration, ondansetron administration does not significantly alter the disease course and should not be administered to this group of children.