BACKGROUND: Ondansetron is increasingly used to prevent emesis in children with acute gastroenteritis; however, the optimal dose is unknown. OBJECTIVE: To determine if higher doses of oral ondansetron are associated with greater efficacy or side effects. METHODS: We analyzed data from a prospective clinical trial performed between January 2004 and April 2005. Data were collected on 105 children with dehydration due to gastroenteritis who received an ondansetron oral disintegrating formulation. The following outcomes of efficacy were analyzed: number of vomiting episodes, volume of oral rehydration fluids consumed, percent weight gain, and the proportions of children who had ongoing vomiting, received intravenous rehydration, and were hospitalized. In addition, the number of episodes of diarrhea was evaluated to measure whether there were dose-dependent side effects. RESULTS: Participants were aged 0.5-8.2 years and the dose ranged between 0.13 and 0.26 mg/kg. There was no significant association between the dose of ondansetron and the outcomes of number of vomiting episodes, volume of fluids consumed, increase in bodyweight, or number of diarrhea episodes/hour. The mean dose of ondansetron (mg/kg) administered was not different amongst those who did and did not have ongoing vomiting, undergo hospitalization, and receive intravenous rehydration. CONCLUSIONS: Within the dose range of 0.13-0.26 mg/kg, higher doses of ondansetron were not superior to lower doses, nor were they associated with increased side effects. Thus, ondansetron in this dose range was shown to result in a similar reduction in emesis in children with acute gastroenteritis.