Abstract Background In coming decades the proportion of very elderly people living in the Western world will dramatically increase. This forthcoming "grey epidemic" will lead to an explosion of chronic diseases. In order to anticipate booming health care expenditures and to assure that social security is funded in the future, research focusing on the relationship between chronic diseases, frailty and disability is needed. The general aim of the BELFRAIL cohort study (BF C80+) is to study the dynamic interaction between health, frailty and disability in a multi-system approach focusing on cardiac dysfunction and chronic heart failure, lung function, sarcopenia, renal insufficiency and immunosenescence. Methods/Design The BF C80+ is a prospective, observational, population-based cohort study of subjects aged 80 years and older in three well-circumscribed areas of Belgium. In total, 29 general practitioner (GP) centres were asked to include patients aged 80 and older. Only three exclusion criteria were used: severe dementia, in palliative care and medical emergency. Two sampling methods for the recruitment of patients were used. Between November 2, 2008 and September 15, 2009, 567 subjects were included in the BF C80+ study. Every study participant was invited to undergo four study visits. The GP recorded background variables and medical history and performed a detailed anamnesis and clinical examination. The clinical research assistant performed an extensive examination including performance testing, questionnaires and technical examinations. Echocardiography was performed at home by a cardiologist. A blood sample was collected in the morning. Follow-up reporting of hard outcome measures including mortality, hospitalization and morbidity was organized. A second data collection is planned after 18 months. Discussion The BF C80+ was designed to acquire a better understanding of the epidemiology and pathophysiology of chronic diseases in the very elderly and to study the dynamic interaction between health, frailty ...