Reirradiation is a challenging field in the treatment of recurrent brain metastases. Because of the elevated risk of radiation toxicity due to previous irradiation, only a limited dose is prescribed. To enhance radiosensitivity, in the present analysis six patients received hypofractionated stereotactic radiotherapy (hSRT) with daily oral administration of the hypoxic sensitizer AK-2123 (sanazole) for progressive brain metastases after previous radiotherapy. The patients received daily oral administration of 1.0 g/day sanazole up to 2 h before radiotherapy. Three partial and three stable responses were observed, with no sanazole-related toxicity, except for a case of mild nausea. Brain failure with subsequent death occurred in one patient. The other patients maintained good performance status until disease progression in other lesions. hSRT with a hypoxic radiation sensitizer appears to have the potential to enhance the efficacy of radiotherapy.