OBJECTIVE We investigated the activity of combination chemotherapy consisting of cisplatin, ifosfamide, methotrexate and vinblastine in patients with metastatic urothelial cancer. METHODS A total of 32 consecutive patients was treated with 30 mg./m.2 cisplatin on days 1 through 3, 1.5 gm./m.2 ifosfamide with mesna on days 1 through 3, 30 mg./m.2 methotrexate and 3 mg./m.2 vinblastine on day 1 plus 5 micrograms./kg. granulocyte colonystimulating factor on days 7 through 11. Courses were repeated every 21 days for a maximum of 6 cycles. RESULTS Major toxicity was granulocytopenia in 56% of patients, including 11 episodes of granulocytopenic fever. Anemia and thrombocytopenia developed in a third of the cases. No other significant toxicity or treatment related death was noted. An objective response was achieved in 20 patients (62.5%, 95% confidence interval 44 to 79). Median time to progression was 7 months and median survival was 13 months. CONCLUSIONS The cisplatin, ifosfamide, methotrexate and vinblastine regimen appeared active in patients with metastatic urothelial carcinoma. This regimen was associated with significant but manageable hematological toxicity and the incidence of mucositis or renal impairment was low. Prospective randomized studies are needed to assess whether the addition of ifosfamide to other active agents will improve the survival of patients with this disease.