A 6-year-old, gelded, Paint horse displayed clinical signs of muscle wasting and limb stiffness for a 6-month period. The horse's clinical signs abated with corticosteroid therapy, but returned upon cessation of treatment. Upon necropsy, severe lesions of aortic thickening and aortic valve rigidity were observed. Histologically, the tunica media of the aorta, coronary arteries, and pulmonary arteries were expanded by foci of elastin fiber calcification and extracellular matrix with lacunae formation. The vascular lesions are comparative to what has been described as medial arterial calcification, seen in humans suffering from chronic renal failure or diabetes mellitus. No exposure to vitamin D-containing plants or feedstuff could be documented at the time of onset or during the period of clinical signs. The current case describes dramatic lesions of arterial medial calcification of the aorta, coronary, and pulmonary arteries of undetermined cause.