Introduction: Overall lifestyle patterns rather than individual factors may exert greater reductions on chronic disease risk and mortality. The objective is to study the association between a Mediterranean lifestyle index and all-cause and cause-specific mortality. Methods: Investigators analyzed data from 20,494 participants in the Seguimiento Universidad de Navarra cohort in 2019. The Mediterranean lifestyle index is composed of 28 items on food consumption, dietary habits, physical activity, rest, and social interactions that score 0 or 1 point; scores theoretically could range from 0 to 28 points. Results: After a median follow-up of 12.1 years, 407 deaths were observed. In the multivariable-adjusted model, high adherence (14 points) to the Mediterranean lifestyle was associated with a 41% relative reduction in all-cause mortality (hazard ratio=0.59, 95% CI=0.42, 0.83) compared with low adherence (3-10 points, p<0.001 for trend). For each additional point, the multivariable hazard ratios for all-cause mortality were 0.95 (95% CI=0.89, 1.02) for food consumption; 1.00 (95% CI=0.92, 1.08) for dietary habits; and 0.73 (95% CI=0.66, 0.80) for physical activity, rest, social habits, and conviviality. Significant interaction with age at last contact (p<0.001) suggested a lower risk for each additional point among participants aged >= 50 years (hazard ratio=0.50, 95% CI=0.34, 0.74), whereas no association was found for participants aged <50 years (hazard ratio=1.15, 95% CI=0.54, 2.44). Conclusions: Adherence to a Mediterranean lifestyle may reduce the risk of mortality in a Spanish cohort of university graduates. Inverse associations were found for the overall Mediterranean lifestyle score and lifestyle block, whereas no associations were observed for the dietary blocks. Future research should consider the Mediterranean lifestyle beyond the Mediterranean diet in different populations for the promotion of healthy longevity. Trial registration: This study is registered at www.clinicaltrials.gov NCT02669602. (c) 2020 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.