Introduction: Differentiation exists between primary muscle-invasive bladder cancer (MIBC) patients and prior history of non-muscle invasive bladder cancer (NMIBC) with progression to secondary MIBC. However, data comparing survival of primary vs. secondary MIBC treated with radical cystectomy (RC) are reporting conflicting results. Therefore, we aim to test the survival difference between primary vs. secondary MIBC treated with RC within our tertiary-case database. Methods: We relied on an institutional tertiary-care database to identify non-metastatic primary and secondary MIBC patients who underwent RC between 2010 and 2021. Specifically, the definition of MIBC consisted of muscle invasion presented in the histological specimen from transurethral resection of the bladder. Kaplan Meier curves depicted two-year overall survival (OS) and recurrence-free survival (RFS). Multivariable cox regression models tested independent predictor status of primary vs. secondary MIBC in analyses addressing OS and RFS. Co-variables consisted of age, sex, pT stage, pN stage, R status, and histology (pure urothelial vs. mixed), as well as intravesical therapy, neoadjuvant chemotherapy and adjuvant chemotherapy. Results: Of 107 MIBC patients treated with RC, 82 (77%) exhibited primary and 25 (23%) secondary MIBC. Median follow-up was 12.8 months. Higher rates of pN0 (60 vs. 40%, p=0.01) were recorded in primary compared to secondary MIBC patients. At two-year follow-up, no statistically significant OS difference was observed between primary vs. secondary MIBC patients (55.3 vs. 46.0%, p=0.45). Similarly, in multivariable cox regression models, secondary MIBC did not predict lower OS compared to primary MIBC (Hazard Ratio (HR): 1.30, 95% confidence interval (CI): 0.59-2.88, p=0.51). At two-year follow-up, no PFS difference was observed between primary vs. secondary MIBC patients (43.2 vs. 41.2%, p=0.81). Similarly, in multivariable cox regression model, secondary MIBC did not predict lower RFS compared to primary MIBC (HR: 1.16, 95% CI: 0.52-2.60, p=0.72). Conclusions: In this tertiary-based institution study comparing, secondary MIBS patients exhibited lower OS than their primary MIBC counterparts. However, no statistically significant OS were observed between these two examined groups. Moreover, no RFS differences were observed between primary vs. secondary MIBC patients. Nonetheless, ongoing patient surveillance is required to identify early MIBC progression in patients with NMIBC. SOURCE OF Funding: None