Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been proposed a companion assay related to the approval of immune checkpoint inhibitors in UBC. We hypothesized that the GA profiles would differ between UBC featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UBC with known PD-L1 expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included with PD-L1 Low (1-49% TC expression) cases excluded from this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UBC featured CD274 (PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amp (P =.05). The gender, age was similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p =.02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach statistical significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UBC cases where a mutational signature could be determined, 10/12 (83%) of PD-L1H and 21/29 (72%) of PD-L1N UBC featured APOBEC signature; 2 PD-L1N featured MMR signature and 6 PD-L1N UBC featured no dominant signature. Conclusions: PD-L1H and PD-L1N subtypes of UBC differ in their genomic profiles:PD-L1N UBC features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UBC but also in designing trials that may combine ICPI with targeted therapies. Limitations include small sample size, possible selection bias and lack of clinical annotation.