The effect of dimethyl sulfoxide (DMSO) on cholesterol-induced atherosclerosis in the rabbit was investigated. Two groups of rabbits were studied: a Control group which received regular chow and an Experimental group which received an atherogenic diet containing 1% cholesterol. DMSO was either omitted or added to the drinking water of both groups in amounts of 2, 4, 5 and 6%. After 3 months all animals were autopsied; the thoracic aorta was examined for atheromatous lesions and the abdominal aorta assayed for total cholesterol content. As expected the thoracic aortas of all rabbits in the Control group were free of atheromatous lesions. With the exception of one rabbit in the Experimental group, all rabbits on the atherogenic diet which did not receive DMSO had extensive aortic lesions covering 82 +/- 5% of the surface area of the thoracic aorta. Aortic lesions were inhibited by about 50% in rabbits on 2% (dose, 1.5 g/kg) DMSO and virtually absent in the majority of rabbits on 4 (dose, 3.5 g/kg), 5 (dose, 5.5 g/kg) and 6% (dose, 9.1 g/kg) DMSO. The food intake of rabbits on the atherogenic diet was not suppressed by DMSO. Changes in the cholesterol content of the abdominal aortas paralleled the presence or absence of lesions in the thoracic aorta. Blood cholesterol levels were greatly elevated in all rabbits on the atherogenic diet and not lowered by DMSO. In conclusion, cholesterol induced atherosclerosis in the rabbit was inhibited by DMSO. This action of DMSO was independent of the hypercholesterolemia and not due to a suppression of food intake. DMSO may provide a useful probe for investigating the underlying mechanism(s) in the development of cholesterol induced atherosclerosis.