Background Acute gastroenteritis is a common childhood condition with substantial medical and indirect costs, mostly because of referral, hospitalisation, and parental absence from work. Aim To determine the cost-effectiveness of adding oral ondansetron to care as usual (CAU) for children with acute gastroenteritis presenting to out-of-hours primary care (OOH-PC). Design and setting A pragmatic randomised controlled trial from December 2015 to January 2018, at three OOH-PC centres in the north of the Netherlands (Groningen, Zwolle, and Assen) with a follow-up of 7 days. Method Children were recruited at the OOH-PC and parents kept a parental diary. Inclusion criteria were: aged 6 months-6 years; diagnosis of acute gastroenteritis; at least four reported episodes of vomiting 24 hours before presentation, at least one of which was in the 4 hours before presentation; and written informed consent from both parents. Children were randomly allocated at a 1:1 ratio to either CAU (oral rehydration therapy) or CAU plus one dose of 0.1 mg/kg oral ondansetron. Results In total, 194 children were included for randomisation. One dose of oral ondansetron decreased the proportion of children who continued vomiting within the first 4 hours from 42.9% to 19.5%, (a decrease of 54.5%), with an odds ratio of 0.4 (95% confidence interval [CI] = 0.2 to 0.7; number needed to treat: four). Total mean costs in the ondansetron group were 31.2% lower ((sic)488 [420] pound versus (sic)709 [610]) pound, and the total incremental mean costs for an additional child free of vomiting in the first 4 hours was -(sic)9 (8) pound (95% CI = -(sic)41 [35] pound to (sic)3 [3]) pound. Conclusion A single oral dose of ondansetron for children with acute gastroenteritis, given in OOH-PC settings, is both clinically beneficial and cost-effective.