Cisplatin based combination chemotherapy remains the mainstay for treatment of advanced urothelial cancer. The combination of 5-fluorouracil and interferon has been found to be effective second line treatment of advanced urothelial cancer. Hence, we tested the combination of cisplatin, 5-fluorouracil and interferon as first line therapy in advanced urothelial cancer. Eligible patients had to have no prior chemotherapy or interferon. Treatment consisted of cisplatin 80 mg/m(2) on day one, followed by 5-fluorouracil 750 mg/m(2) as a daily infusion for 5 days and interferon alpha 2 B 5 MU/m(2) subcutaneously daily on day 1-5 of 5-fluorouracil infusion. Cycles repeated every 21 days. Eighteen patients, of which sixteen were males were enrolled. Median age was 60 years. All patients had transitional-cell carcinoma. The median number of cycles given was 4. Thirteen patients were evaluable for response. Two patients achieved CR and 3 PR for an overall response rate of 28% (95% confidence interval 7% to 49%). Median response duration was 8.3 months. Median survival was 5.5 months. Four patients died secondary to chemotherapy toxicities. Those were GI perforation in one, bronchopneumonia in one, acute renal failure in one and one patient died at home 3 weeks following the third cycle. The above regimen demonstrates excessive toxicity and moderate activity. It cannot be recommended in its present format. Novel anti-cancer agents need to explored.