Background: Some reports suggest that concomitant medications like metformin (M) and statins (S) may enhance efficacy of ICIs in various solid tumors via immune remodeling. Meanwhile other drugs like antibiotics (Abx), proton-pump inhibitors (PPI), H2 blockers (H2b)—may negatively impact outcomes with ICI by affecting the gut microbiome. We report the effect (Abx), (PPI), (H2b), (M)and (S) in our larger cohort of mUC pts treated with ICI; atezolizumab (A), pembrolizumab (P), and maintenance Avelumab (Av). Methods: In our cohort of 474 pts with mUC treated with >/=2 cycles of ICI with A, P or Av between 2015 and 2023, we retrospectively reviewed the use of (Abx), (PPI), (H2b), (M) and (S) and their timing in relation to ICI start (within 60 or 30 days (d) prior to and after ICI start). Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method, outcomes compared using log-rank testing and multivariate (MVA) Cox regression analysis. Results: Of 474 pts, 18.99% received A, 56.75% received P and 24.26% received Av. Median follow-up was 15.6 months. Survival data was available for 455 pts. On MVA Cox regression analysis, Abx use within 60 (d) before ICI start was associated with significantly worse OS while Abx use within 60 (d) post ICI start was associated with significantly worse PFS. PPI use was associated with significantly worse OS and PFS when used 60 (d) prior to ICI use. Metformin was associated with significantly worse PFS when used 60 days prior to ICI start and H2b and Sta did not have any effect on survival outcomes in our cohort. (Table) Conclusions: In our large cohort of pts with mUC treated with either A, P or Av, (Abx), (PPI) and (M) use 60 (d) prior to ICI start were associated with worse OS and PFS. These findings have the potential to influence clinical practice, considering a higher threshold for prescribing antibiotics or PPIs in mUC pts planned to start ICI. These findings warrant further validation in prospective trials.