St. John's Wort is a herbal therapy, shown to be effective in treating mild to moderate depression; a disease common in women in their childbearing years. With a significant proportion of unplanned pregnancies, exposure to St. John's Wort into pregnancy is expected to occur. The purpose of this study was to determine whether exposure to this agent in pregnancy is associated with major malformations. We prospectively collected and followed subjects taking St. John's Wort and compared them to a matched group of pregnant women taking other pharmacologic therapy for depression and a third group of healthy women, not exposed to any known teratogens. We obtained follow-up information on 54 St. John's Wort exposed pregnancies and 108 pregnancies in the two comparator groups. Our results indicated that the rates of major malformations were similar across the three groups, with 5%, 4% and 0% in the St. John's Wort, disease comparator, and health group, respectively (p=0.26), This was not different that the 3-5% risk expected in the general population. The live birth and prematurity rates were also not different among the three groups. Though further large scale studies are still needed, this first study on the effects of St. John's Wort in human pregnancy does provide some evidence of fetal safety.