We have examined effects of atherosclerosis on constrictor responses to serotonin in several vascular beds. In normal monkeys, serotonin produces modest constriction of large arteries. In atherosclerotic monkeys, vasoconstrictor responses to serotonin are greatly potentiated in the limb, cerebral, and mesenteric circulation. The findings may be pertinent to the pathogenesis of vasospasm, which is an important complication of atherosclerosis. Platelets release serotonin when they aggregate. If platelets aggregate at atherosclerotic lesions and release serotonin, and vasoconstrictor responses to serotonin are greatly potentiated in atherosclerotic arteries, serotonin may be an important mediator of vasospasm. To determine whether treatment of atherosclerosis alters vascular responses, atherosclerotic monkeys were fed a low-cholesterol diet for 18 months. This treatment produced marked improvement in vascular lesions, but maximal vasodilator responses were not consistently improved by treatment of atherosclerosis. We speculated that fibrosis of the vessel may prevent improvement of vasodilator responses in vessels with fixed lesions. In contrast, we have found recently that dietary treatment of atherosclerosis abolishes hyperresponsiveness to serotonin in the limb. We conclude that atherosclerosis potentiates vasoconstrictor responses to serotonin and these abnormalities are reversible by dietary treatment of atherosclerosis.