Objective: To determine whether first-trimester exposure to fluoxetine, a selective serotonin reuptake inhibitor commonly used to treat depression and obsessive-compulsive disorders, is associated with increased frequency of fetal malformations. Methods: We evaluated outcomes of all pregnancies identified prospectively with confirmed first-trimester fluoxetine exposure contained in the Eli Lilly and Company worldwide fluoxetine pregnancy registry. These outcomes were compared with historic reports of newborn surveys. Results: Outcomes were available for 796 pregnancies, 37 from fluoxetine clinical trials and 759 from spontaneous reports. Spontaneous abortions were reported in 110 of the 796 (13.8%) pregnancies. Of the remaining 686, malformations, deformations, and disruptions, including those identified after the perinatal period, were reported in 34 (5.0%). No consistent or recurring pattern of abnormalities was observed. Conclusion: Based on comparison with historic reports of newborn surveys, it is unlikely that maternal fluoxetine use during the first trimester of pregnancy results in increased risk of fetal malformations.