The combination of cisplatin and dichloromethotrexate is a pharmacologically rational strategy designed to avoid the nephrotoxicity associated with the systemic chemotherapy of bladder cancer. Of 97 patients with metastatic bladder cancer entered into this study 73 with good renal function received cisplatin and dichloromethotrexate, while 24 with impaired renal function received dichloromethotrexate alone. No responses were noted in the latter group. A 42% response rate (95% exact confidence interval 30.0 to 55.2%), including 9 patients (14%) who achieved a complete response, was observed in the combination group. The toxicity patterns in both groups of patients were consistent with the hypothesis that renal toxicity would be ameliorated with the use of the methotrexate analogue. However, the failure to achieve a higher overall response rate despite near maximum tolerated doses of dichloromethotrexate discourages future studies with this agent. New agents for metastatic bladder cancer should be tested as first line therapy.