Some clinical studies have identified potential adverse patient outcomes associated with RBC storage length. This may in part be due to the release of potentially hazardous bioactive products that accumulate during storage and are delivered at high concentrations during transfusion. In this situation, a proinflammatory tissue microenvironment may be established that can alter immunoregulatory mechanisms. This review highlights some of the potential immunomodulatory effects of stored RBCs that may be responsible for adverse transfusion reactions.