Researchers have reported an association between self-reported antidepressant use and increased risk of ovulatory infertility but could not control for confounding by the drug indication. We evaluated the role of depressive symptoms in the development of infertility. We recontacted a population-based sample of Pawtucket Heart Health Program (PHHP) health survey respondents to perform this case-control study. Self-reported infertility was defined as an inability to conceive after 12 months of unprotected intercourse. Controls were women who reported at least one pregnancy. The index age for infertile women was the age at which they first experienced fertility problems, and for the fertile women it was the age of their first pregnancy. History of depressive symptoms was based on self-report before the index age. Women with a history of depressive symptoms were nearly twice as likely to report infertility relative to women without a history of depressive symptoms before the index age after controlling for potential confounders (90% confidence interval: 0.9-3.2). Our data suggest that depressive symptoms as well as the drugs used to treat these conditions may play an important role in the pathogenesis of infertility. The association between depressive symptoms and infertility should be explored further.