The adverse effects of tumor hypoxia and anemia on the efficacy of radiation therapy have been increasingly recognized. In vitro data indicate that radiation therapy under hypoxic conditions is approximately one third as effective as that under normoxic conditions. There is accumulating clinical evidence of significantly reduced local-regional tumor control and overall survival in anemic patients receiving radiotherapy for head and neck, respiratory tract, pelvic, or genitourinary cancers. In our own study using intraarterial high-dose cisplatin and radiation therapy, we observed that pretreatment hemoglobin level was significantly predictive of complete response (CR) at primary and nodal sites, local-regional failure-free survival, and overall survival by multivariate analyses. With the general lack of success in overcoming the effects of tumor hypoxia through such measures as hyperbaric oxygen and radiosensitizing agents, the focus of clinical research has shifted to directly correcting anemia. A planned randomized trial by the Radiation Therapy Oncology Group will assess the effects of correction of anemia with epoetin alfa on local-regional tumor control and survival in anemic head and neck cancer patients receiving radiation therapy.