Abstract: Objective: To study the association between health-related quality of life (HRQoL) and all-cause mortality in a healthy middle-aged Mediterranean cohort. Methods: We included 15,390 participants -mean age 42.8 years at first HRQoL ascertainment, all university graduates-. HRQoL was assessed with the self-administered Medical Outcomes Study Short Form-36 (SF-36) twice, with a 4-year gap. We used multivariable-adjusted Cox regression models to address the relation between self-reported health and Physical or Mental Component Summary (PCS-36 or MCS-36) and mortality, and their interaction with prior comorbidities or adherence to the Mediterranean diet (MedDiet). Results: Over 8.7 years of median follow-up time, 266 deaths were identified. Hazard ratio (HR) for the excellent vs. poor/fair category in self-reported health was 0.30 (95 % confidence interval (CI), 0.16-0.57) in the model with repeated measurements of HRQoL. Both the PCS-36 (HRquartile4(Q4)vs.Q1 0.57 [95%CI, 0.36-0.90], ptrend < 0.001; HRper+10points: 0.64 [95%CI, 0.54-0.75]) and the MCS-36 (HRQ4vs.Q1 0.67 [95%CI, 0.46-0.97], ptrend = 0.025; HRper+10points: 0.86 [95%CI, 0.74-0.99]) were inversely associated with mortality in the model with repeated measurements of HRQoL. Previous comorbidities or adherence to the MedDiet did not modify these associations. Conclusions: Self-reported HRQoL -assessed as self-reported health, PCS-36 and MCS-36- obtained with the Spanish version of the SF-36 were inversely associated with mortality risk, regardless of the presence of previous comorbidities or adherence to the MedDiet.

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