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The biological mechanisms through which physical activity lowers the risk of cardiovascular disease (CVD) are incompletely understood. We examined the extent to which inflammatory/hemostatic factors (C-reactive protein and fibrinogen), metabolic factors (adiposity, total cholesterol, and HDL cholesterol), and hypertension mediate the association between physical activity and risk of CVD events.Data were collected from a nationally representative sample of 7881 men and women that were linked to a patient-based database of CVD hospital admissions and deaths up to September 2006.A total of 226 incident CVD events (64 fatal) occurred over an average follow-up of 7.2 yr. The risk of CVD decreased in relation to physical activity groups according to current recommendations (at least 30 min of moderate activity five times per week or vigorous activity three times per week). The lowest risks for CVD were seen in participants meeting the recommendations through undertaking vigorous activity (hazard ratio = 0.47, 95% CI = 0.22-0.99), although being physically active below the guidelines also conferred protection (hazard ratio = 0.57, 0.42-0.77). Biological risk factors collectively explained between 39.4% and 22.6% of the cardioprotective effects of moderate and vigorous physical activity, respectively. Inflammation and hypertension tended to explain the largest proportion of variance.Participation in any physical activity, irrespective of meeting current guidelines, was associated with a lower risk of CVD. The inverse association between physical activity and CVD risk is partly mediated by biological risk factors.