Background: There is a lack of the generic data comparing the influence of different diseases on health-related quality of life (HrQoL) in a representative sample of primary care patients. Methods: Patient data were collected in the DETECT (Diabetes Cardiovascular Risk Evaluation: Targets and Essential Data for Commitment of Treatment) study including 55,000 patients. Results: 3,109 patients (33.3% female) with myocardial infarction (MI), stroke or both were compared to patients with a wide range of other diagnoses. Stroke and MI patients revealed a lower HrQoL as compared to patients with other diagnoses. Stroke was associated with strongest quality of life reduction. Multivariate analysis revealed several different determining factors. Conclusions: The reduction of HrQoL of patients with MI and stroke is primarily determined by the CNS insult. These data provide further evidence that early diagnosis and treatment of cardiovascular risk factors is essential to reduce subsequent stroke.