In this study, we determine the clinical impact of 1 dose of oral ondansetron for children with vomiting and evaluate the economic consequences of its use. The strategies compared were administering oral ondansetron in addition to oral rehydration therapy (group A) versus oral rehydration solution alone (group B) in children attended to for vomiting in a pediatric emergency department. The study population was 1871 children between 0 and 14 years of age treated for vomiting during a 2-year period (2009-2010). Outcome measures were need for intravenous rehydration, length of stay in the emergency department, return visits, and hospitalization. Estimates of the costs in the emergency department and hospitalization were derived from administrative databases. During the study period, 580 (31%) of 1871 patients received oral rehydration therapy. Oral ondansetron before oral rehydration solution was used in 109 (18.8%) of 580 patients. An equal number of patients not receiving ondansetron were randomized and analyzed for comparison (group B). Patients of group A had a significantly decreased risk of hospitalization (relative risk, 0.22; 95% confidence interval, 0.08-0.63) and intravenous rehydration (relative risk, 0.31; 95% confidence interval, 0.14-0.63), but there were no differences in the length of stay or return visits to the emergency department. There were no differences in the medical costs between both groups in the emergency department (US $22,078 vs US $21,987, respectively). The hospitalization cost was US $9600 for group A and US $25,079 for group B, providing a 73.7% saving. In conclusion, the administration of oral ondansetron to children with vomiting in the emergency department is clinically effective and results in significant economic savings.