Background and aims: Predictive and prognostic ability of muscle mass in CVD settings is increasingly discussed. The gender-specific effect of skeletal muscle mass index (SMI) on 10-year recurrent fatal/non fatal cardiovascular disease (CVD) event of acute coronary syndrome (ACS) patients was evaluated. Methods and results: In 2006–2009, n = 1000 consecutive patients (n = 222 women), hospitalized at the First Cardiology Clinic of Athens with ACS diagnosis and with symptoms and left ventricular function indicative of heart failure were selected. SMI was created to reflect skeletal muscle mass through appendicular skeletal muscle mass (indirectly calculated through population formulas) divided by body mass index (BMI). In the 10-year follow-up (2016), 55% of ACS patients experienced recurrent fatal/non fatal CVD events (53% in women vs.62% in men, p = 0.04). Patients in the 2nd SMI tertile (mostly overweight) had 10% lower risk for CVD recurrence (women:men rate ratio = 0.87) over their counterparts in the 1st (mostly normalweight) and 3rd tertile (mostly obese). Multivariate analysis revealed that ACS patients in the 2nd SMI tertile presented 46% and 85% lower CVD event risk over their counterparts in the 1st tertile (Hazard Ratio (HR) = 0.54, 95% Confidence Interval (95% CI) 0.30, 0.96, p = 0.002) and 3rd tertile (HR = 1.85, 95%CI 1.05, 2.94, p = 0.03). Gender-based analysis revealed that this trend remained significant only in women. Inflammatory markers had strong confounding effect. Conclusion: A U-shape association between SMI and 10-year CVD event especially in women was highlighted. This work reveals gender-specific remarks for “obesity-lean paradox” in secondary prevention, implying that high muscle mass accompanied by obesity and excess adiposity may not guarantee better prognosis.