<b><i>Background:</i></b> Although TURB of tumor (TURBT) by itself can eradicate a non-muscle-invasive bladder cancer (NMIBC) completely, these tumors commonly recur and can progress to MIBC. It is, therefore, necessary to consider adjuvant therapy in most patients. The primary objective of the present study was to report our experience with EMDA/MMC and BCG, considering efficacy, progression, and recurrence, as adjuvant therapy in NMIBC patients; the secondary objective was to assess the efficacy of EMDA/MMC versus BCG as a comparative treatment. <b><i>Methods:</i></b> Between April 2016 and February 2020, a series of 216 patients, with a diagnosis of intermediate- and high-risk NMIBC after TURBT, underwent adjuvant intravesical therapy. In 26 cases with a failure of the treatment, in patients unfit and unwilling for radical cystectomy, a repeated intravesical therapy was performed (2 had a twice repetition). Out of 244 adjuvant therapies, 140 EMDA/MMC and 104 BCG treatments were done. The following data were collected for each patient: baseline demographics and clinical data and perioperative and postoperative data. Overall patients’ adjuvant intravesical therapies were included in a prospectively maintained institutional database, and a retrospective chart review was performed. We collected data on 2 main outcomes, recurrence-free survival (defined as a negative cystoscopy, cytology, and/or histology at the evaluation time point) and progression-free survival (defined as a negative cystoscopy or a nonprogressive tumor recurrence). <b><i>Results:</i></b> The NMIBC progression rate was higher in BCG than EMDA/MMC but not statistically significant (respectively, 4.2% vs. 2.5%; <i>p</i> = 0.703). In the overall population, the risk of NMIBC recurrence was higher after BCG than EMDA/MMC (<i>p</i> = 0.025). In the subgroups of 59 paired patients with similar characteristics, no difference was observed between groups in NMIBC progression and recurrence. <b><i>Conclusions:</i></b> Our findings suggest that EMDA/MMC and BCG are safe and reproducible approaches as adjuvant treatment in NMIBC. EMDA/MMC permits to achieve a fine oncological management as adjuvant treatment in NMIBC, which is not less than that obtained with BCG.