Thirty patients with measurable metastatic colorectal carcinoma who had not received prior systemic therapy for advanced disease were treated with trimetrexate, a methotrexate analog. Trimetrexate was administered at a median daily dose of 15 mg/m2 (range, 6-22 mg/m2) intravenously for five days every three weeks. No patient achieved a complete or partial response, although minor responses of brief duration occurred in eight patients. The drug was generally well tolerated, thus permitting frequent dose escalations. Common toxic effects included mucositis, dermatitis, and myelosuppression. Our data suggest that trimetrexate given at these doses and in this schedule is not active against colorectal carcinoma.