The low density lipoprotein receptor-related protein (LRP) discovered in 1988 (1) was proposed as a candidate for the postulated apo E-binding chylomicron remnant receptor. Recent results suggest LRP to be a multifunctional cell surface receptor which might have a pivotal function in linkage of diverse metabolic pathways not previously considered to be related. Although biochemical evidence for lipoprotein binding to LRP has been presented (rev in 2), the need to add apo E to lipoproteins to demonstrate lipoprotein binding to LRP has raised doubts as to its lipoprotein receptor function. Therefore, it has yet to be established whether there is a physiologically relevant binding of naturally occurring apo E-containing lipoproteins to LRP. Here we describe cytochemical studies in which naturally occurring apo E-containing lipoproteins carefully isolated by gelfiltration chromatography were found to bind specifically to the cell surface of mouse peritoneal macrophages (MPM). These lipoproteins compete specifically with the binding of activated alpha 2-macroglobulin, which is a generally accepted ligand of LRP, to these cells without previous enrichment with exogenous apo E. We therefore conclude that LRP is indeed a physiologically relevant lipoprotein receptor.