Context: Elevated hypothalamic CRH has been implicated in melancholic major depression in nonpregnant individuals, but the role of placental CRH in maternal prenatal and postpartum depression is largely unexplored. Objective: The objective of the study was to examine the association of maternal midpregnancy plasma CRH levels with prenatal and postpartum depression. Participants: The study included 800 participants in Project Viva, a pregnancy and childhood cohort. Methods: CRH levels were analyzed from blood samples obtained at mean 27.9 wk gestation (± 1.3 SD; range 24.6-37.4 wk) and were normalized on the logarithmic scale. Depression was assessed with the Edinburgh Postpartum Depression Scale (range 0-30 points) in midpregnancy and at 6 months postpartum. We used logistic regression to estimate the odds of scoring 13 or more points on the Edinburgh Postpartum Depression Scale as indicative of major or minor depression. Results: Seventy (8.8%) and 46 (7.5%) women had prenatal and postpartum depression symptoms, respectively. Mean log CRH was 4.93 (± 0.62 SD). After adjusting for confounders, an SD increase in log CRH was associated with nearly 50% higher odds of prenatal depression symptoms (odds ratio 1.48, 95% confidence interval 1.14-1.93). Higher CRH levels during pregnancy were unassociated with greater risk of postpartum depressive symptoms. In fact, there was a suggestion that prenatal CRH levels might be inversely associated with risk of postpartum depressive symptoms (odds ratio 0.82, 95% confidence interval 0.58-1.15). Conclusions: Elevated placental CRH levels in midpregnancy are positively associated with risk of prenatal depression symptoms but not postpartum depression symptoms.