PURPOSE: The T cell-inflamed phenotype correlates with efficacy of immune-checkpoint blockade while non-T cell-inflamed tumors infrequently benefit. Tumor-intrinsic WNT/beta-catenin signaling mediates immune exclusion in melanoma, but association with the non-T cell-inflamed tumor microenvironment in other tumor types is not well understood. EXPERIMENTAL DESIGN: Using The Cancer Genome Atlas (TCGA), a T cell-inflamed gene expression signature segregated samples within tumor types. Activation of WNT/beta-catenin signaling was inferred using three approaches: somatic mutations or somatic copy number alterations (SCNAs) in beta-catenin signaling elements including CTNNB1, APC, APC2, AXIN1, AXIN2; pathway prediction from RNAseq gene expression; and inverse correlation of beta-catenin protein levels with the T cell-inflamed gene expression signature. RESULTS: Across TCGA, 3137/9244 (33.9%) tumors were non-T cell-inflamed while 3161/9244 (34.2%) were T cell-inflamed. Non-T cell-inflamed tumors demonstrated significantly lower expression of T cell inflammation genes relative to matched normal tissue, arguing for loss of a natural immune phenotype. Mutations of beta-catenin signaling molecules in non-T cell-inflamed tumors were enriched three-fold relative to T cell-inflamed tumors. Across 31 tumors, 28 (90%) demonstrated activated beta-catenin signaling in the non-T cell-inflamed subset by at least one method. This included target molecule expression from somatic mutations and/or SCNAs of beta-catenin signaling elements (19 tumors, 61%), pathway analysis (14 tumors, 45%), and increased beta-catenin protein levels (20 tumors, 65%). CONCLUSIONS: Activation of tumor-intrinsic WNT/beta-catenin signaling is enriched in non-T cell-inflamed tumors. These data provide a strong rationale for development of pharmacologic inhibitors of this pathway with the aim of restoring immune cell infiltration and augmenting immunotherapy.