Depression is associated with an increased risk of cardiovascular disease (CVD), coronary heart disease (CHD) and cardiac death. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis function is frequent in major depression and hypercortisolemia may be a mediating factor in these relationships. The aim of this study was to assess HPA axis function measured with the dexamethasone suppression test (DST) in relation to CVD and CHD mortality in a cohort of 382 inpatients with mood disorder admitted to the department of Psychiatry at the Karolinska University Hospital between 1980 and 2000. Death certificates ascertained that 75 patients had died of cardiovascular disease and 30 patients of CHD during the mean follow-up of 18 years. DST non-suppression and higher baseline serum cortisol predicted CVD death. In male inpatients with mood disorder, the DST non-suppressor status was significantly associated with CVD death but not with CHD death. In depressed female inpatients the DST non-suppression was not associated with cardiovascular mortality. Baseline serum cortisol and post-dexamethasone serum cortisol levels at 4:00 p.m. showed a trend to be higher in female CVD/CHD victims. Effect of aging on HPA axis functioning was shown in male CHD deaths. HPA axis dysregulation may be a mediating factor between depression and increased risk of cardiovascular death in male mood disorder inpatients indicating that HPA-axis hyperactivity is a long term risk factor for cardiovascular mortality.