In this study nine patients were treated with 250 mg of methotrexate (MTX) in divided oral doses every 2 weeks. Pharmacokinetic studies carried out on alternate courses showed no alteration with cycles in peak levels of the drug, the half-life of MTX, or the area under the concentration-time curve. Two partial responses (PR) were noted in head and neck squamous carcinoma. Three patients had stable disease and four progressed. Oral high-dose MTX produced predictable exposure of tumors to MTX, although the bioavailability was always less than the equivalent iv dose. Oral MTX was well tolerated by patients, toxicity was minimal, and no evidence of malabsorption of the drug was detected.