Homocysteinemia in humans is associated with vascular complications that increase the risk for atherosclerosis and stroke. Animal studies have shown that the disease is multifactorial and includes lesions associated with the elastin component of the extracellular matrix. In the following experiments we have used the aortas from rapidly growing chicks to assess the cause of the elastin defects resulting from homocysteinemia. Day-old chicks were fed diets containing varying amounts of DL-methionine, DL-homocysteine, homocysteine thiolactone or DL-cysteine for periods up to 9 wk. Three weeks after feeding 2% DL-methionine the plasma methionine was elevated >20-fold, whereas plasma homocysteine was more than 3-fold normal plasma values. The aortas showed severe histopathology, evidenced by the pronounced separation of elastic lamellae with marked smooth muscle proliferation and, in some instances, aneurysms. There was no evidence of decreased desmosine content or a significant reduction in lysyl oxidase in the aortas from the treated groups compared to those from controls. Increasing other dietary factors such as the vitamins required for methionine metabolism had no effect on the development of the vascular lesions. Twenty to 30% of the chicks fed the high methionine diets exhibited severe neurological problems, expressed as tonic contractions or seizures. Electron microscopy revealed disordered aortic elastic fibrils, associated with either an absence of or disrupted assembly of microfibrils. Immunohistochemical studies demonstrated a loss of fibrillin-2 immunoreactivity in the aortas of chicks fed 2% methionine. The studies suggest that elevated plasma methionine or its metabolites disrupt normal microfibril configuration, leading to the assembly of aberrant elastic fibers.