In this study, we show the changes in the wall of the middle cerebral artery of a subject who suffered multiple system atrophy with autonomic failure. An electron-immunocytochemical approach was employed to reveal the presence of endothelin-1. Our results demonstrate the presence of immunoreactive endothelin-1 in the endothelial cells of the intima, vascular smooth muscle cells and macrophages of the media and neointima, and perivascular nerves/axons varicosities at the adventitial-medial border of the artery. It is concluded that endothelin-1 may, therefore, play a number of roles within diseased cerebral artery. The finding of endothelin-1-positive varicosities of autonomic innervation to this artery suggests an influence of neural endothelin on vascular smooth muscle in multiple system atrophy with autonomic failure. However, the presence of features such as neointima formation, wall irregularities and foam cells suggest the coexistence of atherosclerosis.