Background: CYS is strongly recommended for surgically eligible patients with MIBC following cisplatin-based neoadjuvant chemotherapy and is associated with significant surgery-related complications as well as meaningful health-related quality of life impacts. This study described real-world HRU and costs for patients with MIBC, overall and among those who had a CYS. Methods: Adults with MIBC were selected from de-identified IBM MarketScan Commercial and Medicare Supplemental Databases (1/1/2010-2/28/2021) and Multi-State Medicaid Database (1/1/2010-12/31/2019). The index date was defined as the date of initiation of treatment with systemic therapy, radiotherapy, or CYS (used as proxies to identify MIBC) following the first observed bladder cancer (BC) diagnosis. HRU and costs (in 2021 US dollars) were reported per-patient-per-year (PPPY) from the index date to the earliest of metastatic BC, end of continuous insurance eligibility, or end of data. Results: Among 2,249 patients with MIBC (71% male, mean age 65 years, mean [median] follow up = 21 [13] months), 20.3% (N=456) had a CYS (75% male, mean age 63 years, mean [median] follow up = 24 [17] months). In the overall MIBC population, median all-cause total healthcare costs PPPY were $10,524 in the 12-month pre-index period, and $40,980 in the post-index period (Table) with 32% of total healthcare costs PPPY attributable to BC ($13,284). Post-index median all-cause total healthcare costs PPPY were 2.4 times higher among those with CYS ($97,824) relative to the overall MIBC population, with 67% of costs attributable to BC. Patients with CYS had higher all-cause and BC-related HRU PPPY in both inpatient and outpatient settings than the overall MIBC population (TABLE). In addition to the removal of the bladder, CYS surgeries frequently required alteration of other organ systems including prostate and seminal vesical for male; uterus, ovaries, fallopian tubes, and anterior vaginal wall for female patients. Conclusions: This study demonstrates the significant cost and healthcare resource burden associated with CYS in patients with MIBC and further illustrates the need for effective therapies that leave the bladder intact and avoid surgical removal or alteration of otherwise functional organ systems.