Background: Muscle-invasive bladder cancer (MIBC) can present as de novo MIBC (dnMIBC) or progressive MIBC (pgMIBC), the latter occurring in patients with a history of non-muscle-invasive bladder cancer (NMIBC). Retrospective cohort studies have reported varied survival outcomes following RC for pgMIBC versus dnMIBC.Here we aim to pool previous studies and compare survival and pathologic outcomes in patients with pgMIBC and dnMIBC following radical cystectomy (RC), with an investigation of the impact of neoadjuvant chemotherapy (NAC). Methods: A comprehensive literature search was conducted on PubMed and EMBASE databases to identify studies comparing pgMIBC to dnMIBC. Survival outcomes, including cancer-specific survival (CSS), overall survival (OS), and recurrence-free survival (RFS), as well as pathologic outcomes following surgery (rates of ≤pT1, pT0, pT3/T4, and pN+ disease) were compared between pgMIBC and dnMIBC. Results: The analysis included 19 cohorts from 16 studies, categorized into three groups based on NAC status: 1. patients who underwent RC following completion of NAC (RC + NAC only group); 2. patients who underwent RC, with or without NAC (RC +/- NAC group); 3. patients who only underwent RC without NAC (RC only group). Compared to dnMIBC, pgMIBC demonstrated worse outcomes for CSS, OS, and RFS. In the RC + NAC only group (3 cohorts), the hazard ratio (HR) for CSS was 1.52 (95% confidence interval [CI] = 1.05-2.2), the HR for OS was 1.46 (95%CI = 1.05-2.02). Similarly, in the RC +/- NAC group (6 cohorts for CSS and 3 cohorts for OS), the HR for CSS was 1.27 (95%CI = 1.05-1.55), and the HR for OS was 1.27 (95%CI = 1.08-1.51). There were no significant differences observed in pathologic outcomes, including rates of ≤pT1, pT0, and pT3/T4 disease, across all subgroups. However, pgMIBC was associated with a higher risk of nodal metastatic (pN+) disease in the RC + NAC only group (4 cohorts, relative risk [RR] = 1.43, 95%CI = 1.12-1.84). Conclusions: The findings highlight the potentially worse prognosis in patients with pgMIBC compared to dnMIBC, even with the modern use of NAC. The study emphasizes the importance of careful patient counseling, further classification of patients for treatment selection, and the consideration of additional or innovative systemic therapies for pgMIBC.