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Objective: Recent evidence suggests a link between Epstein-Barr virus reactivation and chronic stress due to decreased cellular immune responses. Maternal depression complicates 10% to 20% of pregnancies and is accompanied by stress. We sought to estimate the association of Epstein-Barr virus reactivation with depression in pregnancy., Methods: In this cohort study, prevalence of Epstein-Barr virus reactivation was compared between 100 pregnant women with depression before pregnancy and a computer-generated referent group of 100 healthy women not known to be depressed. We included only those women with documented Diagnostic and Statistical Manual of Mental Disorders depression diagnoses in the current pregnancy. Serum samples were analyzed for presence of Epstein-Barr virus viral capsid antigen, nuclear antigen, and early antigen antibodies. Epstein-Barr virus reactivation was defined by presence of viral capsid antigen or nuclear antigen immunoglobulin (Ig) G, along with early antigen IgG, viral capsid antigen IgM, or both early antigen IgG and viral capsid antigen IgM., Results: Maternal demographics were similar between the groups except for older age (34.1 compared with 32.7 years, P=.05), and lower body mass index (27.3 compared with 28.9, P=.03) among the depressed individuals. Ninety-five percent of the women were seropositive for Epstein-Barr virus. Women with depression were more likely to have Epstein-Barr virus reactivation (48% compared with 30%, P=.01) when compared with referent participants. Epstein-Barr virus reactivation remained associated with maternal depression (adjusted odds ratio 1.97, 95% confidence interval 1.10-3.77, P=.03) after controlling for potential confounders., Conclusion: Women with depression have higher prevalence of Epstein-Barr virus reactivation, possibly due to increased stress., Level of Evidence: II.