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Health-related quality of life (HRQL) instruments have been used to measure HRQL in heart failure patients, but how different instruments compare in the same groups of patients is not known. The purpose of this study was to compare the reliability and validity of three HRQL measures in 211 heart failure patients recruited from clinics affiliated with an urban hospital. Two disease-specific instruments, the chronic heart failure questionnaire (CHQ) and the living with heart failure questionnaire (LHFQ), and one generic instrument, the short-form 12 (SF-12), were administered. Patients reported moderate to low HRQL scores. Floor or ceiling effects were noted in the disease-specific instruments. Internal consistency reliabilities of the CHQ and LHFQ were satisfactory. Construct, convergent, and discriminant validity were supported for each instrument. Each scale and subscale, except for the SF-12 mental component scale, differentiated between patients with New York Heart Association (NYHA) class I, II, and III plus IV; the LHFQ physical subscale was the only measure to differentiate between patients with NYHA class III and IV. All three instruments were satisfactory for measuring HRQL, but the disease-specific instruments were preferable to the generic instrument. The decision of which instrument to use depends on the purpose of the study.