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Objective: The study objective was to evaluate the relationship of health-related quality of life (HRQoL) with fatigue and exercise capacity in coronary artery disease (CAD) patients. Methods: A total of 1072 consecutive CAD patients on admission to a cardiac rehabilitation program were evaluated for HRQoL (36-item Short Form Medical Outcome Questionnaire; SF-36), body mass index, clinical characteristics (New York Heart Association (NYHA) class, angina pectoris class, coronary interventions, treatment with beta blockers, hypertension and diabetes), symptoms of depression and anxiety (Hospital Anxiety and Depression Scale), fatigue (Multidimensional Fatigue Inventory-20; MFI-20), and exercise capacity (bicycle ergometer test). Results: In univariate regression analyses lower scores on all SF-36 domains were associated with greater scores on all MFI-20 subscales. Exercise capacity was associated with all SF-36 domains, except for social functioning and mental health domains. In multivariate regression analyses, after adjusting for age, gender, body mass index, NYHA class, angina pectoris class, hypertension, diabetes, coronary interventions, treatment with betablockers, and symptoms of depression and anxiety, greater limitation due to physical and due to emotional problems, poor social functioning, decreased energy/vitality, worse general health perception, reduced mental component summary and lower global SF-36 score were independently associated with higher MFI-20 general fatigue score. Reduced physical functioning, greater pain, and reduced physical component summary SF-36 scores were associated with greater MFI-20 physical fatigue score. Lower SF-36 mental health score was associated, with greater MFI-20 mental fatigue score. Conclusion: In CAD patients undergoing rehabilitation, poor HRQoL is associated with greater fatigue and decreased exercise capacity independently from mental distress and CAD severity score [ABSTRACT FROM AUTHOR]