OBJECTIVE: To evaluate whether ondansetron or the combination of doxylamine and pyridoxine was superior for the treatment of nausea and vomiting of pregnancy. METHODS: This was a double-blind, randomized, controlled trial in which women with nausea and vomiting of pregnancy were assigned to 4 mg of ondansetron plus a placebo tablet or 25 mg pyridoxine plus 12.5 mg of doxylamine for 5 days. The primary outcome was an improvement in nausea as reported on a 100-mm visual analog scale (VAS). Secondary outcomes were a reduction in vomiting on the VAS and the proportion of patients reporting sedation or constipation while using either study regimen. RESULTS: Thirty-six women (18 in each group) were randomized to either ondansetron or pyridoxine and doxylamine, of whom 13 (72%) and 17 (94%) completed follow-up, respectively. There were no differences among the groups with regard to demographic characteristics or baseline nausea. Patients randomized to ondansetron were more likely to have an improvement in their baseline nausea as compared with those using pyridoxine and doxylamine over the course of 5 days of treatment (median VAS score decreased 51 mm [interquartile range 37-64] compared with 20 mm [8-51]; P=.019). Furthermore, women using ondansetron reported less vomiting (median VAS decreased 41 [interquartile range 17-57] compared with 17 [-4 to 38]; P=.049). There was no significant difference between the groups regarding sedation or constipation. CONCLUSION: Our investigation showed ondansetron to be superior to the combination of pyridoxine and doxylamine in the treatment of nausea and emesis in pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01668069. LEVEL OF EVIDENCE: : I.