Background: Prenatal serotonin reuptake inhibitor (SRI) exposure has been related to adverse newborn neurobehavioral outcomes; however, these effects have not been compared to those that may arise from prenatal exposure to maternal major depressive disorder (MDD) without SRI treatment. This study examined potential effects of MDD with and without SRI treatment on newborn neurobehavior. Methods: This was a prospective, naturalistic study. Women were seen at an outpatient research center twice during pregnancy (26–28 and 36–38 weeks gestational age (GA)). Psychiatric diagnoses were assessed using the Structured Clinical Interview for the DSM-IV; medication use was measured with the Timeline Follow-Back instrument. Three groups were established based upon MDD diagnosis and SRI use: Control (N = 56), MDD (N = 20), or MDD + SRI (N = 36). Infants were assessed on a single occasion within 3 weeks of birth with the NICU Network Neurobehavioral Assessment Scale. Generalized Linear Modeling was used to examine neurobehavioral outcomes by exposure group and infant age at assessment. Results: Full-term infants exposed to MDD + SRIs had a lower GA than CON or MDD-exposed infants and, controlling for GA, had lower quality of movement and more central nervous system stress signs. In contrast, MDD-exposed infants had the highest quality of movement scores while having lower attention scores than CON and MDD + SRI-exposed infants. Conclusion: MDD + SRI-exposed infants seem to have a different neurobehavioral profile than MDD-exposed infants in the first 3 weeks after delivery; both groups may have different neurobehavioral profiles with increasing age from birth. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc.