The molecular mechanisms that protect against the harmful properties of immune complexes and dying cells are not well understood. This review focuses on newly discovered mechanisms for the disposal of immune complexes and apoptotic cells by histidine-rich glycoprotein (HRG). Since HRG is abundantly synthesized by the liver and released into the blood stream at basal levels, it is readily available to engage in the removal of circulating modified self (e.g. apoptotic cells) and non-self (e.g. immune complexes) antigens, whereas other known mechanisms, such as the complement system, require pre-activation and are often accompanied by phlogistic events. These findings suggest clearance mechanism hierarchies. Through its interactions with naked DNA and immune complexes, HRG may mask epitopes recognized by autoantibody-producing B cells (e.g. rheumatoid factors and anti-double stranded DNA antibodies). The latter property may regulate adaptive immune system activation and has important implications for the involvement of HRG in ameliorating autoimmune reactions. Properties of HRG and possible protective actions of HRG-dependent clearance mechanisms are discussed.