OBJECTIVE: To determine if depression contributes to incident heart disease after accounting for genetic, behavioral, and medical factors associated with both conditions. METHODS: We used a prospective twin study with a 12-year follow-up. In 1992, lifetime diagnosis of depression was assessed in 1159 male-male twins and merged with longitudinal health data from the Vietnam Era Twin Registry Study of Aging. Incident heart disease was defined as having myocardial infarction, heart surgery, or angina at 12-year follow-up when twins were 55.4 years (standard deviation, 2.5 years) of age. Risks for heart disease were computed in a logistic regression model that included comparing twins at different levels of phenotypic expression of depression and varying levels of genetic vulnerability at the same time adjusting for pertinent covariates. RESULTS: After adjusting for sociodemographics, co-occurring psychopathology, smoking, obesity, diabetes, hypertension, and social isolation, twins at high genetic risk and exposed to depression remained at greater risk of developing ischemic heart disease (IHD) (odds ratio, 2.55; 95% confidence interval, 1.44-4.49) compared with those at low genetic risk and without phenotypic expression of depression. Odds ratios suggest that twins at genetic liability but without phenotypic expression were at risk of IHD, but the effect was not statistically significant. CONCLUSIONS: A history of depression is a risk factor for incident heart disease after adjusting for numerous covariates. Twins with both high genetic vulnerability and phenotypic expression of depression were at greatest risk of IHD. Trends suggest the genetic contribution to IHD that overlaps with depression may partly explain this association, but studies in larger samples are warranted.