OBJECTIVE: The aim of the present study was to provide a description of the impact of setting on the diagnostic case mix that is identified in consecutive patients presenting with chest pain. METHODS: A cross-sectional study was carried out of patients presenting with chest pain according to setting: general practice, self-referred, referred or arriving by ambulance at the hospital emergency department (ED). GPs from 25 general practices situated in the Flemish part of Belgium were recruited, and the hospital involved was a major teaching hospital in the same area. A total of 320 patients in general practice and 580 patients in the hospital ED were studied. The difference in prevalence rates for the major diagnostic categories was the main outcome measure. RESULTS: Gastrointestinal disorders, musculoskeletal problems and psychopathology are identified more frequently in general practice; and serious lung diseases and cardiovascular diseases in the hospital ED. Within the hospital, there is a strong trend towards increasing frequency of serious cardiovascular diseases including unstable angina (P = 0.01) from self-referred to referred patients and those rushed in by ambulance. The opposite trend was identified for respiratory (P = 0.02) and musculoskeletal (P = 0.07) diseases. The diagnostic case mix in self-referred patients tends to be more similar to the other groups of hospital patients than to patients in general practice. CONCLUSIONS: There is a large difference between the diagnostic case mix presented in general practice compared with the ED and among referral-related subgroups within the hospital emergency department.