Background: Universal screening of pregnant women for postpartum depression has recently been recommended; however, optimal application of depression screening tools in stratifying risk has not been defined. The current study examines new approaches to improve the ability of the Edinburgh Postnatal Depression Scale (EPDS) to stratify risk for postpartum depression, including alternate cut points, use of a continuous measure, and incorporation of other putative risk factors. Methods: An observational cohort study of 4939 women screened both antepartum and postpartum with a negative EPDS screen antepartum(i.e. EPDS < 10). The primary outcome was a probable postpartum major depressive episode(EPDS cut-off 10). Area under the receiver operating characteristics curve(AUC), sensitivity, specificity, and predictive values were calculated. Results: 287 women(5.8%) screened positive for postpartum depression. An antepartum EPDS cut-off95%) at all antepartum EPDS cut-off values from 4 to 8. Discrimination was improved(AUC ranging from 0.70 to 0.73) when the antepartum EPDS was combined with a prior history of major depressive disorder before pregnancy. Limitations: An inability to assess EPDS subscales and a relatively low prevalence of depression in this cohort. Conclusions: Though an antepartum EPDS cut-off score < 5 yielded the greatest discrimination identifying women at low risk for postpartum depression, the negative predictive value was insufficient to substitute for postpartum screening.