While the role of the foam cell in early atherogenesis has been well characterized, much less is known about the interaction between infiltrating macrophages and medial smooth muscle cells (SMC) in chronic atherosclerosis. Our purpose was to determine the effects of soluble macrophage mediators on normal human aortic SMC proliferation and matrix expression. Human aortic SMC in subconfluent culture were exposed to supernatants from activated lipopolysaccharide (LPS) and nonactivated macrophages. SMC proliferation and type-I procollagen expression were determined. Both activated and nonactivated macrophage supernatants exhibited a potent growth inhibitory effect which became apparent at 48 hours. While nonactivated macrophage supernatant had no effect on procollagen expression, activated supernatant inhibited its expression. (33%; p < 0.05) These findings are consistent with the loss of medial SMC and matrix proteins associated with chronic atherosclerosis.