Background: Muscle-invasive bladder cancer (MIBC) is characterized by an overall poor prognosis with a 5-year overall survival (OS) of ~50%. Radical cystectomy (RC) with cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated improved survival in eligible patients and is the current guideline-recommended treatment; however, NAC is underutilized in the real world. The characterization of NAC-treated patients as well as their clinical outcomes in routine practice warrants continued investigation. The objective of this study is to describe the demographic and clinical characteristics, neoadjuvant treatment patterns, and clinical outcomes of patients with MIBC undergoing RC with NAC. Methods: A retrospective cohort study was conducted among adult patients (≥18 years) with MIBC (T2–T4aN0M0, T1–T4aN1M0) diagnosed between 1/1/2016 and 12/31/2021, who received NAC followed by RC, selected from the Syapse Learning Health Network. Patients with another primary tumor ≤3 years prior to MIBC diagnosis, prior partial cystectomy, or prior neoadjuvant radiation were excluded. Patients were followed from NAC initiation (index date) until end of the study period (12/31/2022) or death, whichever occurred first. The analyses included descriptive statistics of demographic and clinical characteristics, NAC treatment pattern, and pathologic complete response (pCR), defined as pT0N0 per pathology reports. Kaplan–Meier analysis was used to describe OS. Results: A total of 140 patients with MIBC met the eligibility criteria of this study (median age 67; 73% male; 90% white; 82% current or former smokers), with a median follow-up of 34 months. Almost all (98%) patients had de novo MIBC and 99% had urothelial histology. At diagnosis, most patients (83%) were staged with T2N0M0 disease; the remaining patients had T1–T4aN1M0 (9.3%) or T3/4N0M0 (7.9%) disease. Median time from MIBC diagnosis to RC was 5 months and median (IQR) NAC treatment duration was 68 days (44-74). The most commonly used NAC regimen was cisplatin + gemcitabine (62.9%), followed by cisplatin + doxorubicin + methotrexate + vinblastine (30.0%). Among patients with pCR data (n=136), 29% achieved pCR. During follow-up, 21% of patients died, and median OS was not reached. Survival rates (95% CI) at 2 and 3 years were 83.8% (77.8–90.2%) and 79.7% (73–87.1%), respectively. Conclusions: Cisplatin-based NAC was widely utilized, with cisplatin + gemcitabine being the most commonly administered regimen. Approximately a third of patients in this neoadjuvant treated RC cohort achieved pCR. Future studies should investigate intermediate or surrogate outcomes in MIBC such as disease-free, event-free, or metastatic-free survival when mature follow-up data is unavailable. Longer follow-up is required to monitor long-term outcomes such as median overall survival.