OBJECTIVE Fludarabine, an adenine nucleoside analogue, and an effective inhibitor of chromosome repair, was previously shown to synergistically enhance radiation-induced regrowth delay in three murine tumors. The purpose of this study was to assess whether fludarabine can increase the therapeutic ratio of radiotherapy in murine tumors, that is, to increase local tumor control without significantly modifying the radiation-induced normal tissue response. METHODS Mice bearing 8-mm tumors in the right thigh (SA-NH sarcoma and MCA-K mammary carcinoma) were given 800 mg/kg fludarabine IP 3 h or 24 h before single doses of photon irradiation. Local tumor control was assessed by the TCD50 assay 100 days after treatment. Acute normal tissue toxicity was assessed in the skin (degree of epilation 30 days after irradiation) and in the jejunum (crypt regeneration assay), and late normal tissue toxicity was assessed by a leg contracture assay 120 days after treatment. RESULTS In both tumors and with both drug schedules, fludarabine enhanced radiation-induced local tumor control (dose modification factors (DMF) of 1.24 (95% confidence limits 1.19-1.31) and 1.26 (95% confidence limits 1.20-1.32) for SA-NH, and 1.38 (95% confidence limits 1.25-1.50) and 1.35 (95% confidence limits 1.22-1.16) for MCA-K tumors). When given 3 h before radiation, fludarabine offered a slight protection from skin toxicity (DMF = 0.83, 95% confidence limits 0.77-0.86) but enhanced jejunum toxicity (DMF = 1.53). When fludarabine was given 24 h before irradiation, the reverse trend was observed (DMF = 1.11 (95% confidence limits 1.07-1.16) and 0.89, respectively). No enhancement of leg contracture was observed for either fludarabine schedule. CONCLUSIONS The data presented here demonstrate that fludarabine can potentiate local tumor control induced by single-dose irradiation. While jejunum sensitization limited the relative effectiveness when fludarabine was administered 3 h before irradiation, a therapeutic ratio greater than one was always achieved when fludarabine was given 24 h before irradiation.