Recent data suggests that HER2-targeted treatment is efficacious in urothelial carcinoma (UC). We investigated the genomic, transcriptomic, and immune landscapes and clinical outcomes in UC segmented by expression. NextGen DNA/RNA sequencing was performed for 4743 UC tumors. A total of 3% (124/4125) of tumors had HER2 IHC and whole transcriptome sequencing (WTS) data. -high and -low tumors were defined by ≥75th and <25th percentiles of expression, respectively. PD-L1 (SP142) positive staining was defined as ≥2+ and ≥5%. HER2 (4B5) positive staining was defined as ≥3+ and >10% or 2+ and >10% with positive HER2 in situ hybridization (ISH). Of the patients who were -high, 79% (61/77) were HER2 positive via IHC. Tumors from lower tract UC had higher expression compared to upper tract UC (50 v 40 median TPM (mTPM), < 0.001). expression was similar between primary and metastatic tumors (47 v 47 mTPM, = 0.95). -high tumors had a higher prevalence of pathogenic mutations in , , and versus -low tumors, < 0.001. -high tumors had higher expressions of ADC target genes (12 v 8 mTPM) and (366 v 74 mTPM) versus -low ( < 0.001), as well as better overall survival from time of tissue sampling than -low (HR 1.71, < 0.001). Our study demonstrated a high concordance between HER2 expression by IHC and gene expression by WTS in UC. Differences in ADC target expression between -high vs. -low UC may provide a rationale for combination treatment strategies with HER2-ADC. The association between high expression and survival advantage warrants further investigation.