Objective: To examine sociodemographic factors, pregnancy-associated psychosocial stress and depression, health risk behaviors, prepregnancy medical and psychiatric illness, pregnancy-related illnesses, and birth outcomes as risk factors for post-partum depression (PPD). Methods: A prospective cohort study screened women at 4 and 8 months of pregnancy and used hierarchical logistic regression analyses to examine predictors of PPD. The study sample include 1,423 pregnant women at a university-based high risk obstetrics clinic. A score of >= 10 on the Patient Health Questionnaire-9 (PHQ-9) indicated clinically significant depressive symptoms. Results: Compared with women without significant postpartum depressive symptoms, women with PPD were significantly younger (p < 0.0001), more likely to be unemployed (p = 0.04), had more pregnancy associated depressive symptoms (p < 0.0001) and psychosocial stress (p < 0.0001), were more likely to be smokers (p < 0.0001), were more likely to be taking antidepressants (ADs) during pregnancy (p = 0.002), were less likely to drink any alcohol during pregnancy (p = 0.02), and were more likely to have prepregnancy medical illnesses, including diabetes (p = 0.02) and neurologic conditions (p = 0.02). Conclusion: Specific sociodemographic and clinical risk factors for PPD were identified that could help physicians target depression case finding for pregnant women.