Background: ICIs have provided advances in the therapy of mUC. However, the objective determination of benefit from ICIs determined by radiographic imaging may take months and may be confounded by pseudoprogression. Peripheral blood cells appear to reflect tumor microenvironment immune infiltrating cells. Given the known prognostic impact of baseline peripheral blood NLR, we aimed to investigate dynamic early changes in NLR as a biomarker of benefit in patients (pts) with mUC. Methods: Deidentified data from mUC pts who were treated with ICIs at Dana Farber Cancer Institute from 2015 to 2020 were reviewed retrospectively. Demographic data (age, gender), setting (untreated vs. post-platinum), sites of metastasis, performance status (PS), platelet count, and NLR at baseline and 3-4 weeks after initiating the ICI were collected. We assessed the association of NLR at baseline and 3-4 weeks after starting the ICI with any regression of tumor (ART) and overall survival (OS). A multivariable logistic regression model and Cox proportional-hazards model was employed to identify the association of NLR changes with ART and OS, respectively, using backward selection. Results: A total of 144 pts were included. The median age was 76 years and 100 (69.3%) were male. Overall, 54.8% (n=79) had ART and the median OS was 15.2 (12.2-23.5) months. 37.5% (n=54) were platinum naive and the remaining received post-platinum ICI therapy. In the multivariable models (Table), an increase in NLR, defined as an increase in NLR by ≥1.0 from baseline at 3-4 weeks was significantly associated with lower odds of ART (Odds Ratio (OR)= 0.80; 95% CI = 0.70-0.90; p = 0.0004) and worse OS (HR = 1.08; 95% CI = 1.05-1.11; p < 0.0001). The presence of liver metastasis was associated with lower odds of ART (OR = 0.30; 95% CI = 0.13-0.70; p = 0.006) and OS (HR 2.73; 95% CI 1.71 - 4.36; p<0.0001). Conclusions: Change in NLR in the first 4 weeks after initiating ICI for mUC was associated with tumor regression and survival in pts with mUC. Change in NLR may assist in early identification of benefit as well as identification of pts who may have progression of disease. Further validation is warranted to facilitate the early discrimination of benefit from ICIs in pts with mUC.