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Aims Although the vital prognosis of heart failure (HF) is generally poor, it varies substantially between patients. This study examined whether health-related quality of life (HRQoL) predicts long-term mortality in HF. It also evaluated the role of generic and disease-specific HRQoL questionnaires. Methods and results We studied 416 patients admitted for HF-related emergencies to four hospitals in Spain in 2000–2001. Health-related quality of life was measured at study baseline with a generic questionnaire, the SF-36, and with a disease-specific one, the Minnesota Living with Heart Failure (MLWHF) questionnaire. Patients were followed prospectively to 2007 to ascertain all-cause mortality. During follow-up, 290 (69.7%) patients died. After adjustment for biomedical, healthcare, and social variables, a poor mental component summary (MCS) score on the SF-36 was associated with higher mortality [hazard ratio (HR) 1.38; 95% confidence interval (CI) 1.06–1.76]. For MLWHF, a poor physical component summary (PCS) score predicted higher mortality (HR 1.31; 95% CI 1.01–1.70). In a stepwise Cox model that included the PCS scores of both the SF-36 and the MLWHF, only the PCS of the MLWHF was retained with P < 0.05. However, when both MCS scores were included, only the MCS of the SF-36 was retained with P < 0.05. Conclusion The SF-36 MCS and the MLWHF PCS predict long-term mortality in patients with HF. Future research should identify the determinants of HRQoL and refine interventions to improve it.