Carbon monoxide (CO) exposure, which results in mean carboxyhemoglobin levels of 10%, enhances the incidence of coronary artery atherosclerosis in female White Carneau pigeons which have been made hypercholesterolemic by addition of cholesterol to their diet. CO is, however, without effect on normocholesterolemic birds. Aortic cholesterol levels are increased by CO exposure but phospholipid and triglyceride levels are reduced in hypercholesterolemic birds. These effects might be due to inhibition of lysosomal enzyme activity. The level of CO exposure, the duration of that exposure, and the level of dietary cholesterol are critically interdependent factors which can influence the extent of CO involvement in the pathogenesis of the disease. CO enhancement of atherosclerosis seems to be significant in the pigeon, during early lesion development when arterial lipid accumulation may be greatest.