Thirty-four chemotherapy-naive, ambulatory patients with advanced renal cell cancer were treated with the non-classical antifol trimetrexate at the intravenous dose of 12 mg/m2 daily x 5 every three weeks (8 mg/m2 qd x 5 for greater than 30% bone marrow previously irradiated). One patient experienced a partial response lasting 24 weeks for a response rate of 3% (exact 95% CI, 0.1 to 15.3%). Toxicity was manageable and primarily myelosuppression, gastrointestinal, and mucosal. Trimetrexate has little activity in advanced renal cell carcinoma at this dose and schedule.