Background and Aim: Mental vulnerability (i.e. a tendency to experience psychosomatic symptoms, mental symptoms or interpersonal problems) is associated with various diseases. This study investigated whether mental vulnerability is associated with hospitalization for depression. Methods: A prospective study was conducted of six cohorts from the population of Copenhagen County, Denmark, with baseline information on mental vulnerability, lifestyle, social factors and comorbidity collected in 1976, 1982-84, 1991 and 1997-98 (N = 11,862). By register-linkage information on hospital contacts for affective disorders were obtained from the Danish Psychiatric Central Register. The association between mental vulnerability and depression was examined using Kaplan-Meier plots allowing for death as competing risk and Cox proportional-hazard models adjusting for possible confounders. Results: The cohort of 11,862 persons yielded a mean follow-up time of 12.3 years with 170 persons hospitalized with depression. The adjusted hazard ratio for hospitalization for depression associated with mental vulnerability was 1.23 (95% CI, 1.16-1.31) per step on the most used 12-item scale. Conclusions: Mental vulnerability may be a risk factor for depression. Early identification and treatment of depression are essential for preventing chronic depression, reduced social functioning and disability. Psychiatric interviews should be used to evaluate whether the criteria for depression are fulfilled, but it may furthermore be relevant to identify persons who may be at risk of developing depression in the long term. The possibility of using, for example, the mental vulnerability scale for such purpose should be further investigated.