How biological factors could mediate the association between physical activity recommendations and cardiovascular disease (CVD) risk was investigated in the Scottish Health Survey (n=7,881 men and women). Being physically active even below current recommendations was associated with a lower risk of CVD. Inflammatory/hemostatic factors (C-reactive protein and fibrinogen), metabolic factors (adiposity, cholesterol and HDL cholesterol) and hypertension explained between 39.4% and 22.6% of the cardioprotective effects of moderate and vigorous physical activity, respectively. Thus, the inverse relationship between physical activity and CVD risk appears to be partly mediated by biological risk factors.