Postoperative nausea and vomiting (PONV) is a common and unpleasant problem for children with burns who are undergoing reconstructive burn surgery. Ondansetron and dimenhydrinate have been found to be effective for the prevention of PONV in other patient populations, but they have not been directly compared in the pediatric population. A prospective, randomized, double-blind, placebo-controlled comparison of ondansetron and dimenhydrinate was performed. One hundred patients with a mean age of 11.8 years who were undergoing reconstructive burn surgery with general anesthesia were randomly assigned to receive either a placebo, 0.1 mg/kg of ondansetron, or 0.5 mg/kg of dimenhydrinate. The 3 groups were well matched for all demographic and procedural variables. The study drugs were given twice, first at the end of surgery and again 4 hours later, to ensure adequate blood levels during the 8-hour study period. Postoperatively, on the basis of the presence and amount of PONV experienced, all patients were assigned a PONV score by a blinded investigator. Statistically significant reductions in the incidence of PONV in the patients who received ondansetron or dimenhydrinate were found, as compared with the results of patients who received placebo. Postoperative vomiting was reduced from 61% in the placebo group to 29% and 40% in the ondansetron and dimenhydrinate groups, respectively, and PONV was similarly reduced from 69% to 47% and 40%, respectively. The differences between ondansetron and dimenhydrinate were not significant. The average cost to our pharmacy for the prescribed dose of ondansetron was $19.34; the cost for dimenhydrinate was $0.90. In this patient population, dimenhydrinate was as effective as ondansetron for the prevention of PONV and postoperative vomiting, and it was much less expensive.