Potential mechanisms responsible for the cardiovascular protection associated with high levels of dietary potassium were investigated in in vitro and in vivo studies. Elevation of extracellular potassium concentration within the physiological range inhibited free radical formation from macrophages and endothelial cells, inhibited proliferation and thymidine incorporation of vascular smooth muscle cells, and reduced platelet sensitivity to thrombin and other agonists. The effects of potassium on several well-characterized animal models of vascular pathology were also studied. Acute elevation of plasma potassium concentration inhibited thrombus formation in the coronary artery of the dog and the carotid artery of the rabbit. In cholesterol-fed rabbits, 6 weeks of diet containing low potassium content increased by approximately 50% (compared with control rabbits) the number of arteries in the myocardium showing signs of arteriosclerotic lesion formation. And in rats and pigs, 4 weeks of eating high potassium-content diet reduced the severity compared with control animals of neointimal proliferation associated with balloon angioplasty. We propose that high levels of dietary potassium provide cardiovascular protection by inhibiting the function of the cells that are responsible for vascular lesion formation.