Human soluble Fas ligand (sFasL) has an apoptotic activity in contrast to murine sFasL. The physiological function of human sFasL is not known, while the pathological consequence of sFasL overproduction has been reported. To understand the physiological function of (human) sFasL, murine and human lymphocytes were treated with sFasL. sFasL treatment significantly decreased CD45RBlo "memory" CD4+ lymphocyte fraction and increased propidium iodide (PI)+ apoptotic CD45RBloCD4+ lymphocytes among murine peripheral lymphocytes. However, sFasL treatment neither decreased CD45RO+ "memory" CD4+ lymphocyte fraction nor increased PI+ CD45RO+CD4+ lymphocytes among human peripheral lymphocytes, suggesting that the deletion of memory cells by sFasL had already occurred in vivo. Patients with systemic lupus erythematosus had sFasL-susceptible "memory" cell fraction suggesting an incomplete deletion of such "memory" cells. These results suggest that the physiological function of human sFasL is to delete the potentially auto-reactive "memory" lymphocytes, which complements membrane FasL (mFasL)-mediated deletion of auto-reactive cells in human beings but not in mice.