Background Skeletal muscle mass (SMM) is inversely associated with cardiometabolic health and the ageing process. The aim of the present work was to evaluate the relation between SMM and 10 year cardiovascular disease (CVD) incidence, among CVD-free adults 45+ years old. Methods ATTICA is a prospective, population-based study that recruited 3042 adults without pre-existing CVD from the Greek general population (Caucasians; age ≥18 years; 1514 men). The 10 year study follow-up (2011-2012) captured the fatal/non-fatal CVD incidence in 2020 participants (50% men). The working sample consisted of 1019 participants, 45+ years old (men: n=534; women: n=485). A skeletal muscle mass index (SMI) was created to reflect SMM, using appendicular skeletal muscle mass (ASM) standardised by body mass index (BMI). ASM and SMI were calculated with specific indirect population formulas. Results The 10 year CVD incidence increased significantly across the baseline SMI tertiles (p<0.001). Baseline SMM showed a significant inverse association with the 10 year CVD incidence (HR 0.06, 95% CI 0.005 to 0.78), even after adjusting for various confounders. Additionally, participants in the highest SMM tertile had 81% (95% CI 0.04 to 0.85) lower risk for a CVD event as compared with those in the lowest SMM tertile. Conclusions The presented findings support the importance of SMM evaluation in the prediction of long-term CVD risk among adults 45+ years old without pre-existing CVD. Preservation of SMM may contribute to CVD health.