Objectives: To evaluate the activity and safety of intravesical instillations of 80 mg epirubicin in a selected patient population with T1G2 primary and multiple superficial bladder tumors. To assess the completeness of the transurethral resection (TUR) at 4 weeks (second look) and to compare the histology of local and review pathology. Methods: One hundred and sixty-nine patients have been histologically assessed both locally and extramurally for T1G2 superficial bladder tumors. Epirubicin (80 mg/instillation) started within 20 days after TUR was administered weekly during the first month and then monthly for another 11 months. Assessments for relapse were carried out according to the standard methods. Results: Histological consistency for T1G2 between local and extramural assessments was found in 85.2% of cases. At the median follow-up time of 38 months, the overall relapse rate was 43.3%. Treatment was very well tolerated: no systemic adverse events were reported and local adverse events were confined to chemical cystitis which in 3% required treatment discontinuation. Conclusions: Epirubicin (80 mg/instillation) appeared effective in the prophylaxis of relapse in primary and multiple T1G2 superficial bladder tumors. A second TUR at 3–4 weeks is necessary in T1 tumors. Excellent concordance between local and review pathology was found.