The Homocysteine and Progression of Atherosclerosis Study (HPAS) is a long term, prospective, blinded, multifactoral clinical study which began in 1991 to study the relationship between elevated plasma homocysteine (HC) as well as a number of other risk factors and PVD progression. The study is divided into two phases, conducted sequentially upon 400 patients with symptomatic lower extremity (LED) and cerebrovascular disease (CVD). The first phase was a three year natural history study in which relationship of progression of peripheral vascular disease to plasma homocysteine and other risk factors was established. The clinical question addressed by the natural history study was: Do patients with symptomatic peripheral vascular disease and elevated plasma homocysteine have more rapid/frequent progression of peripheral vascular disease than patients with symptomatic peripheral vascular disease and normal plasma homocysteine? Progression of disease was assessed by the primary outcome variables of ankle brachial pressure index and degree of carotid artery stenosis, as determined in the noninvasive vascular laboratory, and by secondary outcome variables including vascular death, need for vascular surgery, stroke, myocardial infarction, amputation, and other clinical events. All outcome variables were determined by investigators blinded to the results of plasma homocysteine testing.