Description: Objectives Patients with non-traumatic lower extremity amputation are characterised by high age, multi-morbidity and polypharmacy and long-term complications of atherosclerosis and diabetes. To ensure early identification of patients at risk of amputation, we need to gain knowledge about the progression of diseases related to lower extremity amputations during the years preceding the amputation. Design A retrospective population-based national registry study. Setting The study includes data on demographics, diagnoses, surgery, medications and healthcare services from five national registries. Data were retrieved from 14 years before until 1 year after the amputation. Descriptive statistics were used to describe the progression of diseases and use of medication and healthcare services. Participants An unselected cohort of patients (≥50 years; n=2883) subjected to a primary non-traumatic lower extremity amputation in 2010 or 2011 in Denmark. Results The prevalence of atherosclerosis, hypertension and diabetes was 70%, 53% and 49%, respectively. Among patients with atherosclerosis, 42% had not received cholesterol-lowering treatment even though 87% had visited their general practitioner within the last year prior to amputation. Further, 16% were diagnosed with diabetes at the time of the amputation. The prevalence of cardiovascular diseases increased from 22% to 70%, atherosclerosis from 5% to 53% and diabetes from 17% to 35% over the 14 years preceding major amputation. Of all patients, 64% had been in contact with the hospital or outpatient clinics within the last 3 years, and 29% received a prescription of opioids 3 years prior to the amputation. Conclusion Among patients with non-traumatic lower extremity amputation, one-third live with undiagnosed and untreated atherosclerosis and one-sixth suffer from undiagnosed diabetes despite continuous contacts to general practitioner and the hospital. This study emphasises a need for enhanced focus, among both hospital clinicians and general practitioners, on the early identification of atherosclerosis and diabetes.