The low level of oxygenation within tumors is a major cause of radiation treatment failures. We theorized that anaerobic bacteria that can selectively destroy the hypoxic regions of tumors would enhance the effects of radiation. To test this hypothesis, we used spores of Clostridium novyi-NT to treat transplanted tumors in mice. The bacteria were found to markedly improve the efficacy of radiotherapy in several of the mouse models tested. Enhancement was noted with external beam radiation derived from a Cs-137 source, systemic radioimmunotherapy with an I-131-conjugated monoclonal antibody, and a previously undescribed form of experimental brachytherapy using plaques loaded with I-125 seeds. C. novyi-NT spores added little toxicity to the radiotherapeutic regimens, and the combination resulted in long-term remissions in a significant fraction of animals.