Abstract Objectives To assess survival of patients with muscle-invasive bladder cancer (MIBC) who underwent radical cystectomy (RC) with or without neo-adjuvant chemotherapy (NAC) according to the pathological response at RC. Methods 965 patients with MIBC (cT2-4aN0M0) who underwent RC with or without NAC were analyzed. Among the collected data were comorbidity, clinical and pathological tumor stage, tumor grade, nodal status (y)pN, and OS. Case–control matching of 412 patients was performed to compare oncological outcomes. Kaplan–Meier curves were created to estimate OS for patients who underwent RC with or without NAC, and for those with complete response (pCR), partial response (pPR), or residual or progressive disease (PD). Results Patients with a pCR or pPR at RC, with or without NAC, had better OS than patients who had PD (both p values < 0.001). Moreover, the incidence of pCR was significantly higher in patients receiving NAC prior to RC than in patients undergoing RC only (31% versus 15%, respectively; p < 0.001). Case–control matching displayed better OS of patients who underwent RC with NAC, median survival not reached, than of those who underwent RC only, median 4.5 years (p = 0.023). Conclusions This study showed that patients with MIBC who underwent NAC with RC had a significant better OS than those who underwent RC only. The proportion of patients with a pCR was higher in those who received NAC and RC than in those who were treated by RC only. The favorable OS rate in the NAC and RC cohort was probably attributed to the higher observed pCR rate.