Autoimmunity results when the immune system fails to distinguish between self and non-self factors in the body. The cellular and biochemical mechanisms that underlie development of autoimmunity are only partly understood. One current theory is that autoimmunity can result when there is a failure to clear dying cells from a tissue before they undergo lysis of the plasma membrane. That is, cells that die by apoptosis are thought to be cleared from a tissue by neighboring phagocytic cells, such as macrophages, before the cells have lost their plasma membrane integrity. This rapid removal of early apoptotic cells is thought to prevent induction of an inflammatory response to intracellular macromolecules, thereby allowing for an immunologically silent removal of the dying cells. Hence, any factor or condition that inhibits phagocytosis of early apoptotic cells may trigger or promote an autoimmune response to intracellular components. Depletion of factors required for the efficient phagocytosis of dying cells would have a similar outcome. The recent discovery that the natural anticoagulant protein S is required for efficient uptake of apoptotic cells (Anderson, H.A., Maylock, C.A., Williams, J.A., Paweletz, C.P., Shu, H., and Shacter, E. (2003) Nature Immunology 4, 87-91) reveals a potential new linkage between autoimmunity and coagulation systems. This article will review the dual roles of protein S as an anticoagulant and in regulating phagocytosis of apoptotic cells, with emphasis on exposing a possible novel role in regulating autoimmunity.