<p>Upper tract urothelial carcinoma (UTUC) exhibits poorly defined molecular heterogeneity and lacks reliable biomarkers for subtype classification. We investigated the prognostic impact of luminal-like UTUC defined by GATA3 and FOXA1 immunohistochemistry in 245 surgically resected UTUC cases. The cohort included 183 non-muscle-invasive (NMI) and 62 muscle-invasive (MI) tumors. The Kaplan–Meier and Cox analyses demonstrated that the luminal-like subtype had opposite prognostic implications depending on muscle invasiveness: poorer outcomes in NMI-UTUC but more favorable outcomes in MI-UTUC. To provide biological context, we additionally analyzed independent RNA-seq datasets stratified by <i>GATA3</i> and <i>FOXA1</i> expression. Luminal-like tumors showed consistent upregulation of cell growth and developmental pathways, whereas non-luminal-like tumors, particularly in MI cases, were enriched for immune-related signatures such as antigen presentation and T-cell recruitment. Exploratory biomarker screening also identified one luminal-like gene and three non-luminal-like genes with survival implications. Using a large cohort of patients with UTUC, we establish GATA3 and FOXA1 as robust surrogate IHC biomarkers for luminal-like UTUC. Their prognostic value is dependent on muscle invasiveness, with transcriptomic analyses providing complementary mechanistic insights.</p>