The use of oral hypoglycemic agents to treat adult-onset diabetes has been implicated in an increased incidence of cardiovascular mortality. Since it is likely that altered arterial wall metabolism plays an important role in the atherogenic process and in cardiovascular disease, the primary aim of the present study was to investigate the in vitro effects of two oral hypoglycemic agents (tolbutamide and glyburide) on glucose and acetate incorporation into aortic lipids of the dog. Tolbutamide resulted in a significantly increased incorporation of glucose into total lipids, phospholipids and fatty acids of aorta, but had no apparent effect on acetate incorporation into aortic lipids. In contrast, glyburide significantly decreased glucose incorporation into the total lipid, phospholipid and triglyceride fractions. Acetate incorporation into the triglyceride, free cholesterol, fatty acid and cholesterol ester fractions of aorta also was significantly decreased by glyburide. The data indicate that the oral hypoglycemic agents tolbutamide and glyburide can alter glucose and acetate utilization by arterial tissue. These observations on arterial lipid metabolism provide sufficient justification for further studies directed towards characterizing the effects of oral hypoglycemic agents on the various aspects of arterial wall metabolism.