Thirty patients with advanced metastatic and chemotherapy-refractory urothelial tumors received a combination of fluorouracil (5-FU) and recombinant human interferon alfa-2a. Thirty-six sites of metastases were present in the 30 study patients, and the median Eastern Cooperative Oncology Group performance status was 3 (range, 1 to 4). All patients had failed to respond to primary combined methotrexate/cisplatin-based chemotherapy. Nine (30%; confidence interval, 15% to 47%) of the patients achieved a partial response. The mean duration of response was more than 5.2 months (median, 6 months; range, 3 to 8 months). Two patients who achieved a partial response of 5 and 7 months' duration, respectively, had control of residual disease (one with radiation and one with surgical excision) and have remained disease-free for an additional period of more than 7 and 13 months, respectively. These data suggest that the combination of 5-FU and recombinant human interferon alfa-2a is synergistic, with clinical significance for the treatment of urothelial tumors. The response rate for this combination of drugs is higher than that anticipated for either of these agents used alone. Additional confirmatory trials are needed to evaluate the significance of these findings.