Rapid phagocytosis of non-opsonized particles including apoptotic cells is an important process that involves direct recognition of the target by multiple scavenger receptors including P2X7 on the phagocyte surface. Using a real-time phagocytosis assay, we studied the effect of serum proteins on this phagocytic process. Inclusion of 1-5% serum completely abolished phagocytosis of non-opsonized YG beads by human monocytes. Inhibition was neutralized by pretreatment of serum with 1-10 mM tetraethylenepentamine (TEPA), a copper/zinc chelator. Inhibitory proteins from the serum were determined as negatively charged glycoproteins (pI <6) with molecular weights above 100 kD. A glycoprotein-rich inhibitory fraction of serum not only abolished YG bead uptake but also inhibited phagocytosis of apoptotic lymphocytes or neuronal cells by human monocyte-derived macrophages. Three copper and/or zinc containing serum glycoproteins; ceruloplasmin (CP), serum amyloid P-component (SAP) and amyloid precursor protein (APP), three Alzheimer’s disease associated glycoproteins, were identified and the purified proteins were shown to inhibit the phagocytosis of beads by monocytes as well as phagocytosis of apoptotic neuronal cells by macrophages. Human adult cerebrospinal fluid (CSF) which contains very little glycoprotein, had no inhibitory effect on phagocytosis of either beads or apoptotic cells. These data suggest for the first time that metal-containing glycoproteins present within serum are able to inhibit the scavenger activity of mononuclear phagocytes towards apoptotic cells while this process is unimpeded for the removal of insoluble debris and apoptotic neurones from the central nervous system.