Background: Thymic epithelial tumors (TET) are one of the rarest adult malignancies. Overall, patients have favorable survival outcomes, however a small subset develop metastatic disease. Genomic characterization of this very rare, clinically aggressive TET subset is lacking. Herein, we evaluated the clinical and genomic characteristics of metastatic TET (mTET) compared to a large cohort (n = 117) of primary TET (pTET) from The Cancer Genome Atlas (TCGA). Methods: From 2015 to 2020, 52 pts with mTET underwent clinical CLIA-based sequencing using either whole-exome (n = 35), panel-based testing (n = 13) and/or liquid biopsy (n = 22). The specimen was taken from a metastatic organ (n = 34) or relapsed primary mediastinal mass (n = 14); 4 pts had liquid bx only. Data on pTET was derived from the TCGA. Kaplan-Meier and log-rank test was used for assessment of PFS, OS. Results: The median age was 56 yrs in mTET (range 32-74) vs. 60 yrs (range 17-84) in TCGA data. The M/F (%) was 40/60 in mTET and 48/52 in TCGA, respectively. Of note, 13 mTET pts had other types of cancer prior or concurrent with TET diagnosis (4-breast, 2-bladder, 5-other) in which radiotherapy (n = 4) and/or chemotherapy (n = 3) was administered prior to TET diagnosis. In our cohort, 19 pts had stage IVA and 33 pts had stage IVB (most common metastatic site was liver in 17 pts). WHO histologic classification was: A = 1, A/B = 3, B1 = 4, B2 = 10, B3 = 12, TC = 18, TC with neuroendocrine feature = 3, and lymphoepithelial carcinoma = 1. WHO B3 and TC histologies were more common in our cohort of mTET than in the TCGA cohort (63% (33/52) vs. 17% (20/117), respectively). Pts with TC had worse mOS compare to thymoma (109m vs. 163m, HR = 2.78, P = 0.04). The most common genomic alteration in mTET was TP53 (n = 17, 33%) compared to 3% in TCGA. This was followed by CDKN2A (n = 5, 10%), PIK3CA (n = 4, 8%), CDKN2B (n = 3, 6%) and NF1 (n = 3, 6%). All TP53 missense mut functionality was analyzed with polyphen-2 software and 91.6% (22/24) had 98-100% damaging probability. 70% of pts that harbored TP53 muts were TC (41%) or B3 (29%) histology. Clinically actionable genomic alterations targetable with available or investigational agents (e.g. high TMB; gain-of-function mutations in PIK3CA, CDK4, and mTOR; loss-of-function mutations in NF1) were seen in 23% (12/52) of pts. Conclusions: Patients with mTET are associated with more aggressive WHO histology (B3 and TC). Greater frequency of TP53 mutations are observed in mTET compared to pTET. Clinically actionable genomic alterations are frequently seen in mTET suggesting value in the routine sequencing of these patients.