Six adult patients with squamous cell carcinoma of the head and neck were treated with single low doses of methotrexate (MTX) (30 mg/m2) iv, im, and orally in the form of commercial tablets. A randomized crossover design was employed. Plasma concentrations were measured by a modified EMIT assay over a period of 24 hours following each dose. The mean (+/- SD) parameters following iv MTX were as follows: total-body clearance, 124 (36) ml/minute; Vss, 0.56 (0.18) L/kg; V lambda, 0.69 (0.24) L/kg; and beta-half-life, 3.20 hours. The absolute systemic bioavailability of the oral tablets was 36% (+/- 10%). After im administration, the systemic bioavailability was 93% (+/- 14%). Dose-dependent gastrointestinal absorption is suggested as the mechanism for the low availability of the oral tablets. Administration of MTX by the oral route will require further study to determine the optimal method of dosing.