Background and aims: We prospectively assessed the association between a healthy lifestyle score (HLS) and the risk of type 2 diabetes mellitus (T2DM) in a Mediterranean cohort. Methods and results: We followed up 11,005 participants initially free of diabetes diagnosis in the "Seguimiento Universidad de Navarra" (SUN) cohort. We evaluated the influence of lifestyle related factors based on a score previously related to a lower risk of cardiovascular disease. Only one incident case of T2DM was found among those with a baseline BMI 22 kg/m(2). Therefore, we excluded the BMI item and restricted the analysis to participants with a baseline BMI 22 kg/m(2). We measured the baseline adherence of a HLS that included: never smoking, physical activity, Mediterranean diet adherence, moderate alcohol consumption, avoidance of binge drinking, low television exposure, taking a short nap, spending time with friends and working hours. Incident cases of T2DM were self-reported by participants and confirmed by a physician. Cox proportional-hazards regression models were fitted to assess the association between HLS and the incidence of T2DM. After a median follow-up of 12 years, 145 incident cases of T2DM were observed. Among participants with a BMI >22 kg/m(2), the highest category of HLS adherence (7-9 points) showed a significant 46% relatively decreased hazard of T2DM compared with the lowest category (0-4 points) (multivariable adjusted HR: 0.54; 95% CI: 0.30-0.99). Conclusions: Higher adherence to a HLS, including some factors not typically studied, may reduce T2DM risk. Preventive efforts should preferentially focus on weight control. However, this score may promote a comprehensive approach to diabetes prevention beyond weight reduction. (C) 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.