Since 1972, a large number of studies have shown that intravesical treatment with doxorubicin (adriamycin) is effective against carcinoma in situ and multiple papillary tumors. Furthermore, it significantly reduces the recurrence rate after transurethral resection. Its efficacy has been compared with that of Bacillus Calmette-Guerin (BCG), which is the only treatment accepted by the US Food and Drug Administration for therapy of carcinoma in situ (Tis). In more recent years, a few studies have been performed using intravesical epirubicin in the hope that different properties of the molecule might enhance the activity of the anthracyclines, but produce fewer and milder side-effects. After weekly instillations of epirubicin (50 mg in 50 ml of sterile water) a complete response is achieved in 47% of patients with a histologically proven papillary marker lesion. The prophylactic efficacy of even a single instillation of epirubicin within 6 hours after transurethral resection (TUR) was proved in a randomized study (30863) of the EORTC (European Organization for Research on Therapy of Cancer) Urological Group. A randomized Italian trial (Blinst 4) of chemoprophylaxis after TUR investigated the efficacy of different intravesical administration schedules of epirubicin (50 mg in 50 ml of sterile water). All treatment regimens were more effective than no treatment. The sequential intravesical combination of epirubicin and interferon-alpha-2b has shown, in our personal experience, encouraging clinical results and our laboratory data suggest the synergic activation of the local immune response.