PURPOSE: We aimed at this study to test the value of immediate postoperative intravesical epirubicin instillation in intermediate and high-risk non-muscle-invasive bladder cancer patients. MATERIALS AND METHODS: After approval of Institutional Review Board, 260 patients were randomly allocated into 2 groups, including transurethral resection of bladder tumor (TURBT) alone in control group and TURBT plus immediate postoperative epirubicin (50 mg) in test group. Patients were monitored for postoperative complications. Adjuvant instillation therapy was administered according to risk categorization. Patients were followed every 3 months by cystourethroscopy and urine cytology. The primary end points were recurrence, progression, and/or death from cancer. RESULTS: Of the 260 patients, 236 were eligible and followed for a mean of 29 months. The 2 study groups were comparable regarding perioperative baseline demographic criteria. There was no statistically significant difference between the 2 groups regarding recurrence rate (27.1% vs. 26.2%), interval to first recurrence (16.3 ± 6.6 vs. 16.4 ± 6.4 months) or progression rate to muscle invasion (8.5% vs. 5.9%). Site, size, and number of recurrences were also comparable between the 2 groups. Recurrences and progression-free survival were comparable between the 2 groups (Log-rank P = 0.88 and 0.47, respectively). Postoperative complications were all low-grade according to modified Dindo-Clavian system, with no significant difference in their rate between the 2 groups. CONCLUSIONS: Immediate post-TURBT epirubicin instillation is ineffective in intermediate and high-risk non-muscle-invasive bladder cancer. It neither prolongs time to recurrence and/or progression nor reduces number of recurrences. We advocate strict specification of patient and tumor criteria in which immediate instillation is indicated.