Background: Thymic epithelial tumors (TETs), including thymic carcinomas and thymomas, are rare neoplasms arising in the mediastinum. Chemotherapy is still the mainstay of treatment and few therapeutic options are available for patients with advanced or metastatic TETs. Due to their rarity, the sample size in the previous reports about the genomic profiles of TETs was small and the results varied from study to study, which hinders the development of treatment. Herein, we investigated the comprehensive genomic characteristics of TETs evaluated in a large genomic database profiled in a real-world setting. Methods: Tissue biopsy-based comprehensive genomic profiling was performed in the course of routine clinical care. We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the US (Frampton GM, et al. Nat Biotechnol 2013) and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, which is engaged in a national project for collecting genomic analysis and clinical results from patients. Samples profiled at Foundation Medicine were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated as previously described (Chalmers ZR, et al. Genome Med 2017. Trabucco, et al. J Mol Diagn 2019). Patients’ background including histology, age, and sex were also investigated, and genetic alteration, TMB, and MSI were stratified by them. Results: A total of 794 patients were collected for our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, 414 cases of thymic carcinoma and 308 cases of thymoma were included. CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), CDKN2A (5.8%) and CDKN2B (4.6%) in thymoma. TMB-High (≥ 10muts/Mb) and MSI-High were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Comparison of the thymic carcinoma cohort based on age < 60 vs 60+ years found a significant difference in prevalence of NFKBIA alterations (2.7% age < 60 vs 11.7% age ≥ 60, p = 0.034), while a similar comparison of the thymoma cohort found no significant differences between age groups. An analysis based on sex did not find any significant differences between groups. 55 cases of thymic carcinoma and 17 cases of thymoma were included from C-CAT data. In thymic carcinoma, CDKN2A (27.3%), TP53 (23.6%) and CDKN2B (20.0%) were also frequently altered, while alterations of TSC1 (23.5%) and CD22, LTK, NOTCH1, KMT2A, SETD2, ATM (17.6% each) were found in thymoma. Conclusions: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB, and MSI status of TETs were investigated. We suggest that several gene mutations, TMB, and MSI status might be potential targets for treatment and lead to therapeutic development opportunities, especially in thymic carcinoma.