Background: Nausea and vomiting of pregnancy (NVP) are seen in 50-80% of pregnancies. However, in severe NVP, called hyperemesis gravidarum (HG), medical therapy to reduce nausea and vomiting is inevitable and ondansetron (OND) as an effective drug has recently been proposed. This study evaluated the effectiveness of OND versus metoclopramide (MET) in the treatment of HG. Methods: In this clinical trial study, 83 pregnant women with HG were enrolled in 2011-2012 and randomly divided in two groups. The first group received oral administration of MET and the second group was treated with OND for two weeks. Severity of nausea and vomiting were evaluated according to visual analogue scale (VAS) criteria. Data analysis was done by χ2, Fisher exact test and Student’s t-test. Results: Comparison of the trend of change of vomiting in the two groups during the 14-day treatment showed the OND group had significantly lower vomiting scores versus the MET group (p = 0.042), while there was no significant difference in the trend of nausea. Conclusion: OND has a more favorable effect in controlling severe vomiting.