In Vivo murine tumor experiments were carried out to determine whether 6-thioguanine (6-TG) could enhance the cytotoxic effects of radiation on tumors. The combined effects of single and fractionated x-irradiation were evaluated on the transplanted methylcholanthrene induced fibrosarcoma (Meth-A) in BALB/c mice, a moderately radioresponsive tumor and on the radiation induced fibrosarcoma (RIF) in C3H/He mice, a highly radioresistant tumor. The combined treatment of single administration of 6-TG (25 mg/kg) and of x-irradiation (20 Gy) on Meth-A tumors produced more than 90% tumor control, whereas the radiation alone resulted in less than 5% tumor control. The radiosensitizing effect by 6-TG was higher when the drug was administered either 1 to 8 hr prior to or 24 hr after x-irradiation. The dose modification factor of single dose 6-TG (10 mg/kg) is estimated to be 1.47 for Meth-A tumor and 1.25 for RIF tumor. The tumor control rates of fractionated irradiation alone and with concomitant 6-TG in Meth-A tumors were 14% and 59%, respectively. Based on the studies reported here and well documented pharmacokinetics in humans, it is suggested that combined radiation therapy and 6-TG may provide an enhanced therapeutic effect even in tumor varieties where the drug has no apparent anti-tumor activity on non-irradiated cells.