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KDM6A is a critical part of the COMPASS-like complex. KDM6A deficiency may result in EZH2 dependency. KDM6A deficiency was analyzed by immunohistochemistry on a tissue microarray containing 14,814 samples from 153 different tumor entities and 76 different normal tissue types. In normal tissues, KDM6A staining was ubiquitously seen in nuclei. In tumors, KDM6A deficiency occurred in 58 of 153 tumor categories. KDM6A deficiency predominated in urothelial carcinomas (17.3-42.0%) and was seen in 4-10% of gastric, pancreatic, prostatic, and gallbladder adenocarcinomas, serous endometrial carcinomas, squamous cell carcinomas, papillary renal cell carcinoma, hepatocellular carcinomas, malignant melanomas, and ovarian serous high-grade carcinomas. Reduced or absent KDM6A expression was associated with advanced pT stage (p = 0.0233), high grade (p = 0.0002), and distant metastasis (p = 0.0152) in breast cancer, nodal metastasis in squamous cell carcinomas (p = 0.0498), advanced pT stage (p = 0.0002), nodal metastasis (p = 0.0112), and mismatch repair deficiency (dMMR; p = 0.0147) in colorectal adenocarcinoma, and with dMMR (p = 0.0033) in gastric adenocarcinoma. KDM6A deficiency was significantly more common in tumors from males (4.3%) than from females (1.9%; p < 0.0001). In summary, KDM6A deficiency predominates in urothelial neoplasms but also occurs in many further tumor entities. Whether KDM6A deficient cancers are susceptible to EZH2 inhibitors remains to be seen.