Background To determine whether differences in body composition contribute to sex differences in cardiovascular disease (CVD) mortality, we investigated the relationship between components of body composition and CVD mortality in healthy men and women. Methods and Results Dual energy x-ray absorptiometry body composition data from the National Health and Nutrition Examination Survey 1999-2004 and CVD mortality data from the National Health and Nutrition Examination Survey 1999-2014 were evaluated in 11 463 individuals 20 years of age and older. Individuals were divided into 4 body composition groups (low muscle mass-low fat mass-the referent; low muscle-high fat; high muscle-low fat, and high muscle-high fat), and adjusted competing risks analyses were performed for CVD versus non-CVD mortality. In women, high muscle/high fat mass was associated with a significantly lower adjusted CVD mortality rate (hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P=0.01), but high muscle/low fat mass was not. In men, both high muscle-high fat (HR, 0.74; 95% CI, 0.53-1.04; P=0.08) and high muscle-low fat mass (HR, 0.40; 95% CI, 0.21-0.77; P=0.01) were associated with lower CVD. Further, in adjusted competing risks analyses stratified by sex, the CVD rate in women tends to significantly decrease as normalized total fat increase (total fat fourth quartile: HR, 0.56; 95% CI, 0.34-0.94; P<0.03), whereas this is not noted in men. Conclusions Higher muscle mass is associated with lower CVD and mortality in men and women. However, in women, high fat, regardless of muscle mass level, appears to be associated with lower CVD mortality risk. This finding highlights the importance of muscle mass in healthy men and women for CVD risk prevention, while suggesting sexual dimorphism with respect to the CVD risk associated with fat mass.