Low density lipoprotein (LDL) conditioned by incubation in the presence of rabbit aortic or human umbilical vein endothelial cells (endothelial cell-modified LDL) was degraded by macrophages three to five times more rapidly than LDL incubated in the absence of cells (control LDL). This enhanced degradation occurred mostly via a high affinity, saturable pathway related to the pathway for macrophage uptake of acetylated LDL. Conditioning LDL with cultured aortic smooth muscle cells had a qualitatively similar but smaller effect; conditioning with fibroblasts had no effect. Conditioning very low density lipoproteins or high density lipoproteins with endothelial cells did not affect subsequent metabolism of these lipoproteins by macrophages. Endothelial cell-modified LDL, while degraded more rapidly than control LDL by macrophages, was degraded more slowly by cultured smooth muscle cells and by human skin fibroblasts. Degradation of endothelial cell-modified LDL by macrophages was accompanied by stimulation of cholesterol esterification, inhibition of cholesterol synthesis, and a net increment in total cellular cholesterol content. Thus, a biologically generated modification of LDL is described that markedly alters cholesterol metabolism of macrophages and, consequently, may play a role in foam cell formation during atherogenesis.