Background: Erdafitinib is FDA-approved for patients (pts) with advanced urothelial carcinoma (aUC) with FGFR2/3 mutation or fusion and progression after platinum-based chemotherapy. It is postulated that FGFR3-altered aUC may be a “cold tumor” and associated with non-T cell-inflamed phenotype and, thus, may be less responsive to ICI. We hypothesized that pts with aUC that harbor FGFR2/3 alterations would have lower response and shorter survival on ICI. Methods: We performed a retrospective cohort study of pts with aUC treated with ICI and available genomic data in 11 institutions; pts with pure non-UC, treated with combinations or on clinical trial were excluded. Outcomes (overall response rate [ORR], progression free survival [PFS] and overall survival [OS] were compared in pts with and without FGFR2/3 alterations. PFS and OS was compared using Cox proportional hazards. All analyses were performed in the overall population and also categorized by treatment line (1^st line [1L] vs salvage [2+L]). Multivariable models were adjusted for an internally developed risk score for 1L and Bellmunt risk score for 2+L; p<0.05 was significant. Results: 310 pts met inclusion criteria; 217 pts, 206 pts, and 204 pts were included in ORR, OS and PFS analyses, respectively. Median follow up time was 37 months [mo]. Overall, median age at ICI initiation was 69, 74% men, 85% White, 27% mixed histology, 24% upper tract, 15% liver metastases, 55% ECOG PS 0-1; 101 pts (33% of total population) had FGFR2 or FGFR3 mutation/fusion. ORR to ICI in pts with FGFR2/3 alteration was 25% (95% CI 15-37%) vs 46% (95% CI 38-55%) in pts without such alterations. PFS was shorter for pts with FGFR2/3 alteration (median [m] PFS 4 mo vs 7 mo without such alterations; HR=1.53 [95% CI 1.09-2.15], p=0.015). However, OS was similar in both groups (mOS 14 mo in both groups; HR=1.09 [95% CI 0.75-1.58], p=0.65). ORR, PFS and OS analyses stratified by ICI treatment line (1L vs 2+L) are shown in the Table. Conclusions: In this multisite retrospective study, the presence of FGFR2/3 alterations was associated with lower ORR and shorter PFS in pts with aUC treated with ICI. Limitations include retrospective nature, lack of randomization and central scan review, selection bias, missing data, and possible residual confounding. Findings suggest that FGFR2/3 alterations may impact response and PFS with ICI and might inform discussion on the optimal sequence of therapies in aUC but need external validation and ideally clinical trial data.