OBJECTIVE:To prospectively investigate the association of selective serotonin reuptake inhibitor (SSRI) exposure through critical windows of pregnancy establishment with fecundability and pregnancy loss. DESIGN:Prospective cohort study using longitudinal urine measurements of common SSRIs while women are actively trying to conceive. SETTING:Four clinical sites. PATIENT(S):A total of 1,228 women without uncontrolled depression/anxiety, attempting natural conception while participating in a randomized trial of preconception-initiated low-dose aspirin. INTERVENTIONS(S):Not applicable. MAIN OUTCOME MEASURE(S):Urinary SSRIs (fluoxetine, sertraline, escitalopram/citalopram) were measured while trying to conceive and, for women who became pregnant, at weeks 0, 4, and 8 of pregnancy. Fecundability odds ratios and incidence of pregnancy loss and live birth were estimated. RESULT(S):A total of 172 women (14%) were exposed to SSRIs while trying to conceive. SSRI exposure was associated with 24% reduced fecundability, and accordingly, a nonsignificant 9% lower live birth incidence, with significantly lower live birth in fluoxetine-exposed women. SSRI exposure was not associated with subsequent pregnancy loss, whether exposure was before conception or at 0, 4, or 8 weeks of gestation, although estimates varied by specific SSRI drug. CONCLUSION(S):Women using SSRIs may have more difficulty becoming pregnant, and although SSRI exposure overall was not associated with pregnancy loss, fluoxetine deserves caution and future study. CLINICAL TRIAL REGISTRATION NUMBER:NCT00467363.