PURPOSE: The aim of this quantitative systematic review is to compare the efficacy and side effects of combining one of the 5-HT(3) receptor antagonists (5-HT) with droperidol or dexamethasone for postoperative nausea and vomiting (PONV) prophylaxis. METHODS: We performed a systematic search (Medline, Embase, and the Cochrane Library) for randomized controlled trials that compared the antiemetic efficacy of combining one of the 5-HT with droperidol or dexamethasone vs 5-HT alone. Relevant endpoints were prevention of early (0 to 6 hr), and overall (0 to 24 hr) PONV, and side effects. The articles that could meet the inclusion criteria were scored for inclusion and methodological validity using the three-item, five-point, Oxford-scale. Relative risk and numbers needed-to-treat with 95% confidence intervals were calculated for each combination vs 5-HT alone. The two combinations were then indirectly compared. A random effects model was used. RESULTS: We considered 41 trials for analysis but subsequently excluded eight. Thirty-three trials with data from 3,447 patients were analyzed. Except for early nausea with the 5-HT plus droperidol, both combinations were significantly more effective than 5-HT in preventing early and overall PONV. There was no difference in antiemetic efficacy between the two combinations. The incidence of commonly reported side effects was also similar in the two combination groups. CONCLUSION: We conclude that there is no statistically significant difference in antiemetic efficacy or side effects profile when one of the 5-HT is combined with either droperidol or dexamethasone and that both combination regimens are significantly more effective than 5-HT alone.