Objectives: This paper discusses the effect of antidepressant use on the illness course in three women who were treated for first-onset postpartum depression (PPD) following childbirth. Methods: A report of three cases of early-onset PPD in which bipolarity manifested following antidepressant treatment. Results: There was no past history of psychiatric disturbance but in each case there was a family history of bipolar (BP) disorder. Treatment with antidepressants resulted in a highly unstable illness course characterized by a mixed episode, cycle acceleration, and a postpartum psychosis. However, discontinuation of antidepressants and institution of treatment with mood stabilizers and atypical neuroleptics resulted in sustained improvement and symptom remission. Conclusions: Caution is urged in the use of antidepressants to treat early-onset PPD in women at risk for developing BP disorder due to a family history of bipolar illness.