Rabbits were maintained for 12 weeks on either a control or hypercholesteremic dietary regime, or on comparable diets supplemented with pyridinolcarbamate (PDC) at a level of 30 mg/kg body weight/day. Blood was obtained from all rabbits prior to study and at two-week intervals for analysis of serum cholesterol, phospholipid phosphorus and triglycerides. Animals from each group were sacrificed at 4-week intervals for quantitative assessment of the degree of atherosclerotic involvement of the aorta. All animals in the four groups consumed their entire daily allowance (100 g) of their respective diets, and weight gains throughout the feeding period were comparable in the 4 groups. PDC given with the control chow diet had no effect on serum cholesterol levels but did result in persistent decrease in serum triglycerides and a variable decrease in serum phospholipids during the 12-week feeding period. None of the rabbits on the chow diet, with or without PDC, had any evidence of aortic lesions during the experimental period. Rabbits fed 1% cholesterol administered with chow exhibited markedly elevated levels of serum cholesterol and phospholipids, while serum triglycerides were not significantly different than in the control group. In these animals there was a rapid and progressive increase in aortic atherosclerosis throughout the study, and at 12 weeks plaque involvement was 74 +/- 8% of the aortic surface. Addition of PDC to the 1% cholesterol--chow diet resulted in significantly lowered levels of serum cholesterol and phospholipids, but these remained elevated compared to the control levels. There was also a dramatic reduction in the rate and extent of aortic plaque formation. Thus, after 12 weeks on diet, only 27 +/- 6% of the aortic surface showed evidence of atheroma. The data suggest that PDC significantly decreases the hypercholesteremia resulting from feeding 1% cholesterol to rabbits, and that this may be largely responsible for the antiatherogenic effect of this drug.