Methotrexate, administered orally, is a useful agent when combined with irradiation for the treatment of squamous cell carcinoma of the head and neck. The reported superior effect of the drug, when given by regional intra-arterial infusion, is offset by the high morbidity rate of that technique. Methotrexate and irradiation each have their own specific method of damaging cancer cells and each acts independently on the tumor. When combined for therapeutic purposes, the results to date suggest that the cure rates for advanced T4 No and Stage IV squamous cell cancer of the head and neck are improved.