CONTEXT: Mortality studies have established that cardiovascular disease is the leading cause of death in patients with adrenal insufficiency and the risk is greater than that observed in individually-matched controls. OBJECTIVE: Here we have performed a detailed analysis of cardiovascular morbidity and mortality, taking account of the role of co-morbidities. DESIGN: Retrospective cohort study. SETTING: UK general practitioner database (CPRD). PARTICIPANTS: 6821 patients with adrenal insufficiency (primary, 2052; secondary, 3948) compared with 67564 individually-matched controls, with and without adjustment for comorbidities (diabetes, hypertension, dyslipidaemia, previous cardiovascular disease, and smoking). MAIN OUTCOME MEASURES: Composite cardiovascular events recorded in CPRD and cardiovascular mortality in those participants with linked national mortality data. RESULTS: Hazard ratios (95%CI) for composite cardiovascular events in patients with adrenal insufficiency of any cause were 1.28 (1.20-1.36, unadjusted) and 1.07 (1.01-1.14, adjusted). Increased cerebrovascular events in patients with secondary adrenal insufficiency accounted for most of the increased hazard (1.53 (1.34-1.74, adjusted)) and were associated with cranial irradiation therapy. Cardiovascular mortality data were available for 3547 patients and 34944 controls. The adjusted hazard ratio for ischaemic heart disease mortality was 1.86 (1.25-2.78) for primary adrenal insufficiency and 1.39 (1.02-1.89) for secondary. CONCLUSION: Co-morbidities largely accounted for the increased cardiovascular events but in secondary adrenal insufficiency, cerebrovascular events were independently increased and associated with irradiation treatment. However, the risk of cardiovascular mortality remained increased even following adjustment for co-morbidities in both primary and secondary adrenal insufficiency.