alpha-Interferon combined with 5-fluorouracil results in significant antitumoral activity in metastatic bladder carcinoma refractory to standard MVAC chemotherapy. As a single agent, alpha-interferon is ineffective for invasive or metastatic disease, but appears to contribute to the increased response rate of patients with invasive chemotherapy-refractory disease. Although most patients with superficial bladder carcinoma will not develop invasive disease, patients in complete remission from invasive disease are at high risk for relapse. In vitro assays indicate that fenretinide (4-HPR), alpha-interferon, and 5-fluorouracil possess significant antitumoral activity in human transitional cell carcinoma (TCC) lines. Some features of postchemotherapy-refractory TCC are similar to those of initial superficial disease (sensitivity to biological therapy). The biological study of patients with residual postchemotherapy disease may permit the development of strategies which will prevent the recurrence of malignancy within the bladder following an initial complete remission, in addition to developing strategies for the selection and treatment of patients with high risk superficial disease.