A primary culture of cells derived from uninvolved and atherosclerotic intima of human aorta was used to elucidate the role of cyclic nucleotides in atherogenesis. The cells cultured from fatty streaks and atherosclerotic plaques had a 2- to 8-fold lower cyclic AMP level and a 1.5- to 2-fold higher level of cyclic GMP compared with those of a grossly normal intima. Medial cells cultured from nonlesioned and atherosclerotic aortic segments showed no differences in the cyclic nucleotide concentrations. Reduction of the intracellular cyclic AMP with 2'-deoxyadenosine or a cyclic GMP elevation with its dibutyryl derivative, or liposomes containing cyclic GMP stimulated the uptake of [3H]thymidine and protein synthesis in the cells cultured from unaffected intima. On the contrary, a rise of the intracellular cyclic AMP caused by adenylate cyclase activators, a phosphodiesterase inhibitor, dibutyryl cyclic AMP, and liposomes containing cyclic AMP inhibited cell proliferation and protein synthesis. Elevation of the intracellular cyclic AMP stimulated the hydrolysis of lipids which led to reduction of lipid levels in the cells cultured from atherosclerotic lesions. The results of this study corroborate the existence of a relationship between the alterations of intracellular cyclic nucleotide levels and the metabolic disorders occurring in atherosclerosis.