The aim of this study was to examine the concurrent effects of vital exhaustion and depression on the development of cardiovascular disease (CVD) morbidity. The sample of this representative, 4-year longitudinal study comprised 2,725 participants (43.56% male, Mage = 58.39 years, SDage = 14.39 years). Individuals being treated for hypertension (n = 277) and cardio- and/or cerebrovascular incidents (n = 131) for the first time during the follow-up period were compared with participants never treated for CVD (n = 2,317). Joint principal component analysis was conducted on the items of the vital exhaustion (shortened Maastricht Questionnaire) and depression (shortened Beck Depression Inventory) measures simultaneously resulting in 3 components representing depression, vital exhaustion, and sleep difficulties. The role of these 3 components in predicting the incidence of CVD morbidity was examined using logistic regression-controlling for traditional risk factors such as sex, age, education, body mass index, smoking, alcohol use, and physical inactivity. In the multivariate analyses, vital exhaustion (OR = 1.20, CI = 1.03-1.39, p = .021) and sleep-related problem (OR = 1.16, CI = 1.00-1.33, p = .044) scores proved to be independent predictors of treatment initiation for hypertension, while sleep-related difficulties predicted CVD event incidence (OR = 1.27, CI = 1.06-1.52, p = .009). However, depressive symptomatology factor scores were not associated with either cardiovascular outcome in the regression analyses. Vital exhaustion and depressive symptomatology showed a different pattern in their relationship with CVD incidence, with vital exhaustion being the more robust predictor. These results suggest that the 2 constructs are not identical and that vital exhaustion deserves consideration when planning and implementing interventions to reduce CVD risk. (PsycINFO Database Record