Proteinase inhibitors have been implicated in brain development and in degenerative processes such as Alzheimer's disease. Low-density lipoprotein receptor-related protein (LRP) is a multifunctional cell-surface receptor that binds activated forms of the proteinase inhibitor, alpha 2-macroglobulin (alpha 2M) and apolipoprotein E. Solubilized plasma membranes of human cerebral cortical gray matter were subjected to affinity chromatography on alpha 2M-methylamine-sepharose. A single receptor was purified; this protein was LRP as determined by molecular mass, peptide structure, and immunoreactivity with monoclonal and polyclonal antibodies. In adult human brain, LRP immunoreactivity was abundant on neuronal cell bodies and proximal processes. Other cells within the neuropil, including glia and microvascular cells (endothelium and pericytes), were immunonegative. Weak LRP immunoreactivity was identified in a perivascular pattern corresponding to the location of astrocytic foot processes. The distribution of LRP in the central nervous system is consistent with the potential function of this receptor in the regulation of proteinase activity, cytokine activity, and cholesterol metabolism.