Background: Mesothelin (meso) is overexpressed in many solid tumors and has been used as a target for anticancer therapy. Limited data is available on meso expression in TETs and its clinical correlates. Standard treatments have limited efficacy for patients with advanced TETs, especially thymic carcinoma (TC) after failure of platinum-based chemotherapy. There is an urgent need to identify novel therapeutic targets. In view of early results demonstrating benefit in therapeutic targeting of meso, we characterized meso expression in TETs. Methods: Patients with histologically confirmed thymoma (T) or TC and available tumor tissue who were enrolled in clinical trials at the National Cancer Institute between December 2007 and December 2013 were included. Meso expression was assessed by immunohistochemistry (IHC) using monoclonal antibody 5B2 (Novocastra/Leica, Bannockburn, IL) by a pathologist who was blinded to histological subcategory (T vs. TC) and clinical outcome. IHC staining of > 50% was labeled as positive and ≤ 50% was considered negative. Associations between meso expression and patient characteristics were assessed. Results: 71 cases (42 TC; 29 T consisting of 3 WHO subtype AB, 2 B1, 13 B2 and 11 B3) were included in this series. Meso expression localized to tumor cell membrane was observed in 19 (45%) TC and 1 (3%) T. Median age and gender distribution of meso-positive vs. meso-negative TC was: 55 (21-73) vs. 50 (20-74) years and 11M/8F vs. 10M/5F respectively. Meso-expressing TC included 12 of 16 (75%) poorly differentiated carcinomas, 3 of 11 (27%) squamous cell carcinomas, 1 of 2 (50%) basaloid cancers and 0 of 8 neuroendocrine tumors (including atypical carcinoids). Median overall survival was significantly higher in meso-positive TC compared to meso-negative TC (not reached vs. 48 months; p=0.03). Extra-thoracic metastases were present in 13 of 19 (68%) meso-positive TC and 17 of 23 (74%) meso-negative TC. Conclusions: This is the largest series of meso expression in TC. Meso expression was detected in 45% of TC and associated with a significantly higher overall survival. Further studies are needed to assess the role of meso as a potential therapeutic target in TC.