In this article, the authors examined whether physical activity predicted cardiovascular disease (CVD) independently of well-known cardiometabolic risk factors in men and women. The study included 5,882 adults from the 1999 to 2004 United States National Health and Nutrition Examination Survey. The participants were divided according to the volume of their moderate-to-vigorous intensity physical activity: active (≥150 min./week), somewhat active (30 to 149 min./week), and inactive (<30 min./week). Inactive participants were 52% more likely compared to active participants to have CVD (p<0.05) after adjustment for the basic confounding variables. Both physical activity and cardiometabolic risk factors were independent predictors of CVD (Ptrend<0.0001). These results suggest that physical activity is associated with CVD, independent of the common cardiometabolic risk factors, in both men and women.