TNF-alpha (TNF) is produced primarily from macrophages and promotes numerous inflammatory reactions associated with atherosclerosis including the induction of vascular adhesion molecules and the recruitment and proliferation of monocyte/macrophages. There are two receptors known to elicit TNF responses, termed p55 and p75. Since p55 is thought to play the primary role in inflammatory processes, we postulated that the absence of p55 in mice would protect against atherosclerosis. In contrast, C57BL/6 mice lacking p55 had aortic sinus lesion sizes 2.3-fold larger than C57BL/6 wild type mice when fed an atherogenic diet (37,123 +/- 3485 microm2 versus 16, 688 +/- 2887 microm2, respectively, p < 0.0004). Plasma lipid levels were not different between strains. A 3-fold increase in the uptake and degradation of acetylated low density lipoprotein for p55-null as compared with wild type mice was demonstrated in cultured peritoneal macrophages. Immunohistochemical staining for scavenger receptor protein in the aortic sinus was more intense in lesions from the p55-null mice as compared with wild type controls. Our results support the concept that increased scavenger receptor activity contributes to excessive fatty streak formation. We conclude that TNF p55 receptors protect against atherosclerotic lesion development in the mouse.