SummaryBackground: We investigated whether differential responsivity to tricyclics (TCA) compared to serotonin specific reuptake inhibitors (SSRI) occurred in our clinical population of women with postpartum depression. Method: Sequential records (N = 35) of women with non-psychotic, non-bipolar, postpartum-onset major depression were reviewed to determine drug response. Response was defined as 50% reduction in the initial depression score by week 8 of treatment. Results: The response rate was 67% for TCA was 79% for SSRI. The five nonresponders to TCA were treated with an SSRI, and four (80%) were effectively treated. Discussion: This naturalistic data obtained from our clinic supports that SSRI are superior to TCA for the treatment of postpartum major depression. The difference in percent response (12%) is similar to that of other studies in which TCA were compared to SSRI for treatment depression in women.