Background: Response rates to ICIs in pts with mUC remain modest at around 20% and there are no reliable biomarkers to select pts most likely to respond to ICI. It is an unmet need to define factors associated with PrimRes (progressive disease (PD) clinically and/or radiologically after at least 2 cycles of ICI) to spare pts from unnecessary treatment and the associated physical and financial toxicity. PrimRes to ICI has not been well defined in mUC pts and we sought to study predictive factors in our real-world cohort. Methods: We retrospectively reviewed 335 pts at the Cleveland Clinic who received ≥ 2 cycles or at least 6 weeks of ICI with pembrolizumab (P) or atezolizumab (A) between 2015 and 2023. Pt characteristics such as age, sex, race, BMI, primary site (bladder vs upper tract UC (UTUC)), and antibiotic (Abx) use before or after start of ICI and pre-treatment platelet to lymphocyte (PLR) ratios (divided into quartiles) were collected. PrimRes was defined as pts who had clinical and/or radiologic PD or death from disease within 14 weeks (time period of 1^st assessment with imaging) of ICI initiation. Pts with PrimRes were compared to rest (responders, stable disease and subsequent PD). Multivariate cox regression models were used to identify factors associated with PrimRes. Results: Of the 335 pts, 129 (38.5%) pts had PrimRes based on our criteria. Median age was 73 yrs (35-95). PLR quartiles were clarified as (<149, 149-207, 207-308, ≥308). In our multivariate regression model, we found that pts with PLR ≥308 had a significantly higher chance of PrimRes compared to those with PLR <149 (Hazard Ratio (HR): 2.49; 95% CI: 1.22-5.15; p = 0.0133). Being underweight (BMI < 18.5) was associated with significantly higher rates of PrimRes than normal weight pts (HR: 6.91; 95% CI: 1.55-48.81; p = 0.0211). Abx use within 60 days post ICI start (HR: 2.29; 95% CI: 1.38-3.83; p = 0.0015) and UTUC (HR: 0.46; 95% CI: 0.25-0.83; p = 0.0099) were associated with PrimRes to ICI. Conclusions: In our large cohort of pts with mUC receiving ICI, we report that PLR ≥308, BMI < 18.5, use of Abx within 60 days post- ICI, and UTUC were associated with development of PrimRes to ICI. Ongoing genomic and immune correlates from tissues collected from our cohort will help us better understand the mechanisms of PrimRes to ICI. Validation and harmonization with more datasets and prospective studies can inform future steps towards patient-directed approaches.