OBJECTIVE: Medial vascular fibrosis contributes to arterial stiffening and reduced compliance, increasing the risk of cardiovascular events. We undertook the first comprehensive histopathologic study of medium-to- large caliber blood vessels (carotid, coronary, dorsalis pedis, internal mammary, iliac, mesenteric, pulmonary, and renal arteries) in 100 autopsy subjects to characterize medial fibrosis in relation to cardiovascular risk factors. METHODS AND RESULTS: Masson Trichrome staining of vascular tissue microarrays (TMAs) was digitally analyzed to determine the percent fibrosis (% collagen) of over 700 vascular segments. The percent fibrosis of the tunica media was strongly correlated within subjects across all systemic blood vessels (average r=0.53), suggesting that fibrosis is a global process independent of the predilection of the vessel towards the development of atherosclerosis. Hypertension, diabetes, age and poor renal function were significantly associated with increased systemic vascular fibrosis (ptextless or =0.03). By multivariable analysis, only poor renal function (p=0.003) was an independent predictor of higher levels of fibrosis. Finally, in a subset of 13 individuals we observed a significant correlation between pre-mortem pulse pressure and systemic vascular fibrosis (ptextless0.001). CONCLUSIONS: This study demonstrates that vascular fibrosis is a global process associated with diseases of aging and elevated pulse pressures.