OBJECTIVE: To examine whether spouses of patients with severe sepsis are at increased risk for depression independent of the spouse's presepsis history, whether this risk differs by sex, and is associated with a sepsis patient's disability after hospitalization. DESIGN: Prospective longitudinal cohort study. SETTING: Population-based cohort of U.S. adults over 50 yrs old interviewed as part of the Health and Retirement Study (1993-2008). PATIENTS: Nine hundred twenty-nine patient-spouse dyads comprising 1,212 hospitalizations for severe sepsis. MEASUREMENTS AND MAIN RESULTS: Severe sepsis was identified using a validated algorithm in Medicare claims. Depression was assessed with a modified version of the Center for Epidemiologic Studies Depression Scale. All analyses were stratified by gender. The prevalence of substantial depressive symptoms in wives of patients with severe sepsis increased by 14 percentage points at the time of severe sepsis (from 20% at a median of 1.1 yrs presepsis to 34% at a median of 1 yr postsepsis) with an odds ratio of 3.74 (95% confidence interval: 2.20, 6.37), in multivariable regression. Husbands had an 8 percentage point increase in the prevalence of substantial depressive symptoms, which was not significant in multivariable regression (odds ratio 1.90, 95% confidence interval 0.75, 4.71). The increase in depression was not explained by bereavement; women had greater odds of substantial depressive symptoms even when their spouse survived a severe sepsis hospitalization (odds ratio 2.86, 95% confidence interval 1.06, 7.73). Wives of sepsis survivors who were disabled were more likely to be depressed (odds ratio 1.35 per activities of daily living limitation of sepsis survivor, 95% confidence interval 1.12, 1.64); however, controlling for patient disability only slightly attenuated the association between sepsis and wives' depression (odds ratio 2.61, 95% confidence interval 0.93, 7.38). CONCLUSIONS: Older women may be at greater risk for depression if their spouse is hospitalized for severe sepsis. Spouses of patients with severe sepsis may benefit from greater support and depression screening, both when their loved one dies and when their loved one survives.