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Introduction Thymic epithelial tumors (TETs) are rare neoplasms with different prognosis lacking consistent molecular alterations possibly leading to targeted therapy. We collected a consecutive series of TETs aimed at investigating the mutational status of druggable genes ( EGFR, c-KIT, KRAS, BRAF, PDGFR-alpha and − beta , HER2 and c-MET ) and the expression of ALK and PD-L1. Patients and methods One hundred twelve consecutive cases of TETs and relative clinico-pathologic features were collected. Immunohistochemical expression of ALK (clone D5F3) and PD-L1 (clone E1L3N), molecular analysis of EGFR (exons 18–21), c-KIT (exons 9,11,13,14,17), KRAS (exon 2), BRAF (exon 15), PDGFR-alpha (exon 12) and -beta (exons 12, 14, 18), HER-2 (exons 19 and 20) and c-MET (exons 14, 17, 18, 19) mutations were performed. Immuno-molecular results were then statistically matched with clinico-pathologic characteristics. Results Patients were male in 54% of cases, with a median age of 61 years (range 19–83) and affected mainly by thymoma (78%) in stage II (45%). At molecular analysis, there were 4 c-KIT mutations (occurring in exon 11 V559A, L576P, Y553N and exon 17 D820E) in thymic carcinomas (type C), but not in other tumor types (p = 0.003). No mutations were detected in other genes and none case was ALK positive. Twenty-nine (26%) cases were PD-L1 positive (65% of thymic carcinomas and 18% of thymomas). High PD-L1 expression was statistically associated with WHO classification stage type C ( p < 0.001) and Masaoka stage III–IV disease ( p = 0.007). In univariate analysis, WHO classification type C, advanced Masaoka stage and absence of myasthenia, but not PD-L1 expressions were correlated with worse survival; at multivariate analysis, only WHO type C confirmed its negative prognostic role. Conclusion A subset of TETs as thymic carcinomas can harbor c-KIT mutations and elevated PD-L1 expression that could represent targets of potential therapeutic use. [ABSTRACT FROM AUTHOR]