Background: Using comprehensive genomic profiling (CGP), we queried whether FGFR3-driven mUCB could be further defined by additional genomic alterations (GA) and biomarkers of response to immunotherapies. Methods: DNA from FFPE tissues of 1,576 mUCB underwent hybrid-capture based CGP to evaluate all classes of genomic alterations. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined by principal components analysis of optimal homopolymer loci. Results: 385 (24%) of the 1,576 UCB featured GA affecting FGFR1-4. Of the FGFR3 GA identified in mUBC (FGFR3mut), 77% were SV, 2% were amplifications, 18% were fusions/rearrangements, and 4% had more than 1 GA type. When compared with a cohort of 1,275 FGFR3 WT mUCB, the GA/tumor and frequency of TERT GA were similar. GA in TP53 and RB1 were more common in FGFR3 WT than FGFRmut, whereas cell cycle GA (e.g., CDKN2A) were more common in FGFR3mut tumors. Genes associated with DNA repair were altered in both groups, with ARID1A GA more frequent in FGFR3 WT, KDM6A GA more frequent in FGFR3mut, and BRCA1/2 GA less frequent overall and similar in both groups. Targetable ERBB2 GA were significantly more common in FGFR3 WT cases. Targets in the MTOR pathway, including GA in PIK3CA and TSC1, were also more common in FGFR3mut mUBC. MSI-High status was extremely rare in both groups. The median TMB was higher in FGFR3 WT, and samples more often had TMB of ≥10 mut/Mb or ≥20 mut/Mb. Conclusions: CGP reveals both similarities and differences in the genomic landscapes of FGFR3mut and FGFR3 WT mUBC. In the 2% of mUBC with FGFR3 driver GA, other targetable GA affecting kinases or the MTOR pathway are present. As evidenced by TMB, the opportunity for immunotherapies remains significant.