In many types of malignant disease, therapy has been developed to the degree of providing some frequency of permanent control. The significant advances in the treatment of acute leukemia in man by chemotherapy (1–6), however, continue to be overshadowed by an almost consistent failure to achieve cure. The potential explanation has, at times, been considered to be reinduction of leukemia by an etiologic agent, but two arguments weigh against this. First, other malignant conditions (e.g., Hodgkin's disease), which produce infectious-like clinical syndromes, may conceivably be caused by a viral or other infectious agent and yet be curable. Second, both the premortem and necropsy studies of leukemic patients in complete hematologic remission have revealed tumor-cell infiltrates in various organ systems (7–9); the logical inference from this is that failure to eradicate the cellular phase of the disease is primarily responsible for relapse. One probable cause of resistance to chemotherapy is the presence of mitotically dormant or slowly dividing cells (10, 11). Experimentally, such cells are refractory to chemotherapy (12), as is anticipated because the effect of antimetabolites is dependent upon cell replication (nucleic acid synthesis). A second mode of re-sistance unrelated to the rate of cell division is the development of a drug-fast state secondary, perhaps, to induced or selected alterations in enzyme concentrations (13, 14). Lastly, although not investigated in the studies described herein, the failure to achieve adequate drug levels in certain sites such as the central nervous system (15–17) is recognized as a deterrent to complete leukemic cell elimination. These experiments were designed to study the radiosensitivity of murine leukemia L1210 under conditions in which leukemic cells are refractory to chemotherapy. To determine if cross resistance were present, the survival curves of drug-resistant leukemic cells were examined. Materials and Methods Male DBA/2 mice weighing 20 to 25 g and approximately ten weeks old were used in all experiments and were provided water and laboratory chow ad libitum. The leukemia L1210 strains were carried as ascites lines with weekly transfer by intraperitoneal route. Radiation dose-survival curves were obtained by the Hewitt technic (18, 19). The leukemic cells were irradiated either in vivo or in vitro in cold saline suspension, and a cell count was performed on the irradiated cells. The in vivo irradiations were administered on Day 3 following transplantation before ascites formation was present to assure oxygenated conditions. Serial two- to fourfold dilutions of irradiated cells were prepared with intraperitoneal inoculation (0.1 ml volume) of 9 to 11 mice per dilution. The dilutions for each radiation dose were selected to include levels killing all (or most) or none (or few) of the recipient mice.