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<i>Background:</i> Hypoxia is recognized as a key feature of cancer growth and is involved in various cellular processes, including proliferation, angiogenesis, and immune surveillance. Besides hypoxia-inducible factor 1-alpha (HIF-1α), which is the main mediator of hypoxia effects and can also be activated under normoxic conditions, little is known about its counterpart, HIF-2. This study focused on investigating the clinical and molecular landscape of HIF-2-altered urothelial carcinoma (UC). <i>Methods:</i> Publicly available next-generation sequencing (NGS) data from muscle-invasive UC cell lines and patient tumor samples from the MSK/TCGA 2020 cohort (<i>n</i> = 476) were interrogated for the level of expression (mRNA, protein) and presence of mutations, copy number variations, structural variants in the <i>EPAS1</i> gene encoding HIF-2, and findings among various clinical (stage, grade, progression-free and overall survival) and molecular (tumor mutational burden, enriched gene expression) parameters were compared between altered and unaltered tumors. <i>Results:</i> 19% (7/37) of UC cell lines and 7% (27/380) of patients with muscle-invasive UC display high <i>EPAS1</i> mRNA and protein expression or/and EPAS1 alterations. <i>EPAS1</i>-altered tumors are associated with higher stage, grade, and lymph node metastasis as well as with shorter PFS (14 vs. 51 months, <i>q</i> = 0.01) and OS (15 vs. 55 months, <i>q</i> = 0.01). <i>EPAS1</i> mRNA expression is directly correlated with that of its target-genes, including <i>VEGF, FLT1, KDR, DLL4, CDH5, ANGPT1</i> (<i>q</i> < 0.001). While there is a slightly higher tumor mutational burden in <i>EPAS1</i>-altered tumors (9.9 vs. 4.9 mut/Mb), they are enriched in and associated with genes promoting immune evasion, including <i>ARID5B, SPINT1, AAK1, CLIC3, SORT1, SASH1</i>, and <i>FGFR3</i>, respectively (<i>q</i> < 0.001). <i>Conclusions</i>: HIF-2-altered UC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-promoting genes.