Background: Thymic epithelial tumors (TETs) are rare and tend to have an indolent disease course. Follow-up consists of physical examinations and routine imaging (CT scans) with no currently available biomarkers to complement surveillance. This study aimed to assess the utility of ctDNA in MRD detection and disease monitoring in TETs. Methods: From Nov 2020 till Feb 2022, ctDNA analysis using a tumor-informed mPCR-NGS (Signatera) assay was performed on 29 patients (pts) with primary (pTETs) or metastatic TETs (mTETs). For pts with early-stage disease, the baseline ctDNA was measured 4-8 w post-surgery and repeated q3m. For mTETs, ctDNA was measured at the first visit, and then q3m with interval CT scan q3-4 m. ctDNA was quantified as mean tumor molecules (MTM)/mL of plasma. All pts had at least one measurement (up to 4). GraphPad was used for statistical analysis. Results: Of 29 pts overall, 9 pts were excluded at the time of analysis for various reasons; a) insufficient specimen (n=5), b) presence of concurrent active cancer (n=2), and c) final report delay (n=2). Of 20 evaluable pts, 7 pts had pTETs and 13 mTETs. The median age was 50 yrs (range, 17-72), and WHO histology distribution of AB=3, B1=5, B2=9, B3=12, TC=3. History of autoimmune disease and second malignancy (not active at the time of obtaining ctDNA) was reported in 33% (n=9) and 40% (n=8) of evaluable pts, respectively. Of 13 metastatic pts, 6 had stage IVA with pleural-only metastasis, 7 pts had Stage IVB with 2 extra-thoracic (liver, adrenal), and 5 with intrathoracic (lung, chest wall, and LNs) involvement. From 7 pTETs, 6 pts had R0 resection with undetectable post-operative ctDNA, while R1 resection with detectable ctDNA was reported (0.47 MTM/mL) in one pt. In mTETs, the mean level of ctDNA in pts with the stable disease was 0.18 MTM/mL (0.1-0.2), pleural-only progression 1.26 MTM/mL (0.1-1.9), and progressive disease (primary and/or pleural) 7.67 MTM/mL(5.04-9.5). Comparing the mean level of ctDNA in clinically stable metastatic pts with those who had progression, pts with pleural-only progression did not have a significantly higher level of ctDNA (p=0.51). In contrast, pts with primary and/or pleural progression had significantly higher levels of ctDNA (p=0.02). The level of ctDNA correlated with tumor size. An increase of 4-6mm in tumor size was associated with an approximate 0.2 MTM/mL increase in ctDNA or making the undetectable status detectable. Conclusions: The ctDNA level correlates well with the tumor volume in mTETs. In pTETs, ctDNA was negative following R0 resection but not in the R1, supporting its potential use as a surrogate biomarker for MRD. This is a pilot study, and the expansion of these data is ongoing to validate the utility of ctDNA testing in these settings. If validated, ctDNA may augment or minimize the routine use of CT scans for disease monitoring in resected and mTETs.