Trimetrexate is a nonclassical folate antagonist. It was evaluated in 43 patients, previously not exposed to chemotherapy, with incurable and/or demonstrated progression of squamous cell head and neck cancer following surgery and/or radiotherapy. Trimetrexate was initially administered at 8 mg/m2 intravenous (IV) daily for 5 days, repeated every 3 to 4 weeks with dose adjustments depending on patient tolerance. Thirty-eight of the 43 patients entered in this study were evaluable for response. The 28 males and 10 females had a median age of 60 years. Their median performance status on the Zubrod scale was 1. Thirty-seven patients (97%) had received prior radiotherapy. The disease had metastasized in 84% of the patients with dissemination primarily to the subcutaneous soft tissue (40%). Ten patients (26%; with a 95% confidence interval of 12% to 40%) achieved a partial response (PR) with a median duration of 12.2 weeks (median time to PR was 3.2 weeks). The median survival of the 43 patients was 17.3 weeks with 10 patients alive at last follow-up. Hematologic grade 3 to 4 toxicities included leukopenia (19%), thrombocytopenia (9%), and granulocytopenia (5%). Nonhematologic grade 3 to 4 toxicities possibly attributable to trimetrexate treatment included stomatitis (7%). © 1988.