The content of cAMP and cGMP was measured in the intima and media of unaffected and atherosclerotic areas of human aorta in a short-term organ and cell cultures. In an organ culture the cAMP content in fatty streaks and atherosclerotic plaques is significantly (2 to 7-fold) lower than in unaffected intima. The cGMP level in atherosclerotic lesions is 1.5 to 3-fold higher than normal. The content of both cyclic nucleotides in the media underlying fatty streaks and plaques is the same as in the normal tissue. Similar alterations of cAMP and cGMP levels were seen in the cells cultured from atherosclerotic lesions. Cholera toxin, methylisobutylxanthine and forskolin as well as dibutyryl cAMP inhibit by 2-7-fold[3H]thymidine uptake into intimal cells cultured from atherosclerotic human aorta. These agents also decrease cholesteryl ester and triglyceride levels and do not affect the content of phospholipids and free cholesterol in the cells cultured from atherosclerotic lesions.