Background: To compare overall survival (OS) outcomes in pN1-3 disease at the time of radical cystectomy (RC) for muscle invasive bladder according to the neoadjuvant chemotherapy (NAC) status. Materials and Methods: This multicenter study included 450 consecutive patients undergoing RC for muscle-invasive urothelial bladder cancer with pN1-3 pM0 disease from 2010 to 2019. NAC consisted in platinum-based chemotherapy. The primary endpoint was the comparison between NAC and non-NAC in terms of death from any cause. OS was assessed using the Kaplan–Meier method and multivariate Cox proportional hazards regression was used to estimate adjusted hazard ratios. Results: Median age was 69 years. Patients receiving NAC were younger (p = 0.051), and more likely had downstaging to non-muscle invasive disease (10.7% versus 4.3%, p = 0.042). Median OS was 26.6 months. NAC patients had poorer OS compared with those who did receive NAC (Hazard ratio (HR) 1.6; p = 0.019). The persistence of muscle-invasive bladder in RC specimens was also significantly associated with OS (HR 2.40). In the NAC cohort, the two factors independently correlated with OS were the number of positive lymph nodes (p = 0.013) and adjuvant chemotherapy (AC) (HR 0.31; p = 0.015). Conclusions: Persistent nodal disease in RC specimens after NAC was associated with poor prognosis and lower OS rates compared with pN1-3 disease after upfront RC. In this sub-group of NAC patients, AC was independently associated with better OS.