CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. At sites of chronic inflammation as seen in certain infections, autoimmune diseases, allograft rejection, graft-versus-host (GVH) disease and treatment of cancer patients with high doses of interleukin-2, significant damage to the endothelial cells has been known to occur, which leads to the toxicity or pathogenesis associated with the disease. The exact mechanism of endothelial cell damage is not clear, although, it has been widely speculated that immune cells may play a critical role. Studies from our laboratory have used interleukin-2 (IL-2) induced vascular leak syndrome (VLS) as a model to investigate the role of cytolytic lymphocytes in the direct cytotoxicity of endothelial cells. Cytotoxic T lymphocytes (CTL), double-negative (DN) T cells and natural killer (NK) cells upon activation express high levels of CD44 and mediate efficient MHC-unrestricted TCR-independent lysis following ligation of CD44. Such CD44-mediated cytotoxicity may play an important role in protection against viral infections and cancer. However, it could also cause non-specific tissue injury. For example, dysregulation in the interaction between activated cytotoxic lymphocytes expressing CD44 and endothelial cells bearing the appropriated ligand such as the hyaluronate (HA), could lead to endothelial cell lysis. Furthermore, such endothelial cell injury could lead to the pathogenesis associated with a variety of clinical diseases.