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Although numerous health-related quality-of-life instruments are available to measure patients’ quality of life, few studies have compared these measures directly to determine how they function in the same group of patients.The purpose of this study was to empirically compare psychometric properties of the Chronic Heart Failure Questionnaire (CHQ), the Minnesota Living with Heart Failure Questionnaire (LHFQ), and the General Health Survey Short-form-12 (SF-12).A convenience sample of 211 patients with heart failure completed baseline questionnaires; 165 patients completed the entire 26-week study.Patients completed telephone interviews at baseline and at 4, 8, and 26 weeks after baseline. To compare mode of administration, a subset of patients (n = 173) completed face-to-face and telephone interviews.Patients reported low-to-moderate health-related quality-of-life overall. Reliability of the three instruments was satisfactory. Responsiveness to changing condition, as evaluated by analysis of variance, receiver operating curve characteristics, and the minimal clinically important difference method, indicated that the CHQ and LHFQ were more responsive to changing conditions than the SF-12. No major differences were noted between the scores of the face-to-face interviews and the baseline telephone interviews. The LHFQ and SF-12 were easier and took less time to administer than the CHQ.While all three instruments were reliable and valid, the CHQ and LHFQ were more sensitive than the SF-12 in detecting clinically important changes over time.