Oral methotrexate (MTX) was administered to a group of 48 patients with advanced head and neck tumors prior to radiation therapy in a nonrandomized manner. A second group of 75 similar patients were randomized to intravenous (i.v.) MTX plus radiation or radiation alone. Three‐year survival rates by life table analysis show no significant statistical difference between i.v. MTX plus radiation or radiation alone. Those treated with oral MTX plus radiation have a statistically significant improved survival. The degree of tumor regression in the oral MTX group was correlated with survival. No similar correlation could be found in the intravenous MTX group. The use of either form of MTX correlated with a lower rate of distant metastasis.