MTX-CF therapy was administered in 13 patients with advanced renal cell carcinoma. 2 patients were treated with MTX single agent therapy at a dosage of up to 750mg/m2 per cycle and a short CF rescue of 48 hours. They showed partial remissions along with severe toxicity including gastrointestinal symptoms and bone marrow depression. 11 patients were treated by combination of MTX/CF, vincristine, bleomycin and an alkylating agent (either peptichemio or cyclophosphamide). In this latter group, patients with a glomerular filtration rate of more than 70 ml/min received 150 to 400 mg/m2 per cycle MTX. Patients with decreased renal function (glomerular filtration rate less than 70 ml/min) received 35 to 100 mg/m2 per cycle MTX. Two out of 7 patients with decreased glomerular filtration rate achieved remissions of more than 50%, two achieved remissions of less than 50% and two patients achieved static disease. Only one patient in the group of 4 patients with normal renal function showed a remission of more than 50%. Median survival time of patients in partial remission or with static disease was 24 months, of patients showing progression was 5 months. This difference is highly significant (p < 0.001). These results seem to justify further investigations of MTX/CF therapy in hypernephromas, even in the presence of impaired renal function.