Previous studies from our laboratory demonstrated that CD44 knockout mice exhibit marked decrease in interleukin (IL)-2-induced vascular leak syndrome (VLS), thereby suggesting a role for CD44 in VLS. In the current study, we tested whether treatment with mAbs against CD44 or hyaluronic acid (HA), the ligand for CD44, can abrogate IL-2-induced VLS. Interestingly, administration of HA caused a marked increase in IL-2-induced VLS in the lungs and liver of C57BL/6 mice. In contrast, use of anti-CD44 mAbs reduced IL-2-induced VLS in the lungs and liver. Treatment with HA enhanced the IL-2-induced edema and lymphocytic infiltration in these organs and caused marked increase in IL-2-induced lymphokine-activated killer (LAK) cell activity, whereas administration of anti-CD44 mAbs caused a significant decrease in edema and LAK activity but similar levels of lymphocytic infiltration. Anti-CD44 mAbs, but not HA caused marked downregulation of CD44 expression on LAK cells. These studies demonstrate that molecular targeting of CD44 may serve as a useful tool to selectively alter the LAK activity and to prevent endothelial cell injury induced by IL-2.