Context: Women experiencing depression have difficult psychosocial functioning, and recent data suggest an earlier onset of menopause. Understanding the biological mechanism for the impairment of reproductive function associated with depression is important. Objective: The objective of the study was to determine whether a lifetime history of depression is associated with reduced ovarian reserve as reflected in serum levels of the granulosa cell product, inhibin B. Design: Residual serum samples from a subset of patients in the Harvard Study of Cycles and Moods were collected. Setting: Patients were recruited from seven Boston-area communities. Patients: Women with or without a history of major depression, based on structured clinical interviews for Diagnostic and Statistical Manual of Mental Disorders, fourth edition, were enrolled. A subset of patients who had provided an early follicular phase blood specimen at study enrollment and two or more other samples over the first 18-month period of follow-up were included. Intervention: There were no interventions. Main Outcome Measure: Serum inhibin B levels were measured. Results: Serum FSH levels were higher in women with a history of depression, whereas inhibin B levels did not differ between groups. Body mass index and age were significantly and inversely related to serum inhibin B levels. Smoking history was noted, for the first time, to have a significant negative association with inhibin B levels. Conclusions: Smoking has a direct negative effect on ovarian reserve, as suggested by decreased serum inhibin B levels. In contrast, effects of depression on the reproductive axis may occur at the level of the pituitary and/or hypothalamus rather than at the gonadal level, as suggested by increased serum FSH levels.