There is a strong correlation of plasma cholesterol levels with the risk of coronary heart diseases as shown by epidemiologic studies. This study was undertaken to evaluate the effect of plasma cholesterol lowering on the progression of atherosclerosis in the homozygous Watanabe heritable hyperlipidemic (WHHL) rabbit. The effect of cholesterol lowering, which was accomplished by thermofiltration (on-line plasma separation with plasma filtration at 39 degrees C) was evaluated by comparison between treated and untreated control groups. Thermofiltration reduced significantly the mean plasma level of total cholesterol (284 vs. 655 mg/dl, P = 0.0005) and the percent aortic area occupied by atherosclerotic plaque (15.0 vs. 44.2%, P = 0.0003). The total lipid and cholesterol contents in the aortas in the treated group were also significantly lower than those in the control group. Microscopically, thickness measurements of the lesions showed that the mean thickness of the fibrous cap and the ratio of the thickness of the intima to that of the media were smaller for the treated group than the control group. This study demonstrated the slowing or stopping of the progression of atherosclerosis by lowering the plasma total cholesterol level in WHHL rabbits.