Short-term exposure to the alkyl-lysophospholipid, rac-2-methyl-1-octadecyl-glycero-(3)-phosphocholine (ET-18-OCH3) or the photosensitizing dye, Merocyanine 540 (MC540) and light kills a wide range of leukemia and some solid tumor cells but is relatively well tolerated by normal pluripotent hematopoietic stem cells as well as certain classes of committed progenitor cells. Both ET-18-OCH3 and MC540-mediated photodynamic therapy (PDT) have been used as purging agents in preclinical models of autologous hematopoietic stem cell transplantation and are currently undergoing phase I/II clinical testing for the same purpose. We report here that ET-18-OCH3 synergistically enhances the MC540-mediated photoinactivation of leukemia cells but only minimally reduces the survival of normal granulocyte-macrophage progenitors. Therapeutic indices are most favorable when MC540-mediated PDT precedes incubation with ET-18-OCH3 and when purging is followed by cryopreservation. Taken together, these data suggest that combination purging with alkyl-lysophospholipid and MC540-mediated PDT may provide a simple, versatile, and effective means of eliminating large numbers of leukemia cells from autologous bone marrow grafts without causing excessive damage to normal hematopoietic stem cells.