OBJECTIVE: To perform a systematic review and meta-analysis to determine whether taking antiemetic drugs reduces vomiting and decreases the need for further intervention in children with gastroenteritis without causing significant adverse effects. DATA SOURCES: Computerized databases, reference lists, and expert recommendations. STUDY SELECTION: Prospective controlled trials evaluating medication use in children with vomiting from gastroenteritis. INTERVENTION: Antiemetic drug therapy. MAIN OUTCOME MEASURES: Emesis cessation, use of intravenous fluid for rehydration, hospital admission, return to care, and medication adverse effects. RESULTS: The 11 articles that met the inclusion criteria evaluated various antiemetic agents: ondansetron (n = 6), domperidone (n = 2), trimethobenzamide (n = 2), pyrilamine-pentobarbital (n = 2), metoclopramide (n = 2), dexamethasone (n = 1), and promethazine (n = 1). Meta-analysis of 6 randomized, double-masked, placebo-controlled trials of ondansetron demonstrated decreased risk of further vomiting (5 studies; relative risk [RR], 0.45; 95% confidence interval [CI], 0.33-0.62; number needed to treat [NNT] = 5), reduced need for intravenous fluid (4 studies; RR, 0.41; 95% CI, 0.28-0.62; NNT = 5), and decreased risk of immediate hospital admission (5 studies; RR, 0.52; 95% CI, 0.27-0.95; NNT = 14). Diarrheal episodes increased in ondansetron-treated patients in 3 studies. Ondansetron use did not significantly affect return to care (5 studies; RR, 1.34; 95% CI, 0.77-2.35). CONCLUSIONS: Ondansetron therapy decreases the risk of persistent vomiting, the use of intravenous fluid, and hospital admissions in children with vomiting due to gastroenteritis. Future treatment guidelines should incorporate ondansetron therapy for select children with gastroenteritis.