Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate the efficacy and safety. Methods: Between March 2016 and December 2016, patients with histologically confirmed TET who progressed after platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The trial was registered with ClinicalTrials.gov, number NCT02607631. Results: 33 patients were enrolled, 26 with thymic carcinoma (TC) and 7 with thymoma (T). 19 (57.3%) patients received ≥ 2 prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-13) and median follow up was 6.3 months (ranges, 1.4-9.9). Of 33 patients, 8 (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was not reached for 7 T and 6.2 months for 26 TC. The most common adverse events of any grade include dyspnea (33.3%), chest wall pain (30.3%), anorexia (21.2%) and fatigue (21.2%). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (12.1%), myocarditis (9.1%), myasthenia gravis (6.1%), thyroiditis (3.0%), ANCA-associated rapidly progressive glomerulonephritis (3.0%), colitis (3.0%), and subacute myoclonus (3.0%) except anemia (3.0%). 8 (24.2%) patients (5 T, 3 TC) discontinued study treatment due to irAE, which were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (87.5%). Conclusions: Pembrolizumab showed promising antitumor activity in refractory or relapsed TET. Given the relatively high incidence of irAEs, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. Clinical trial information: NCT02607631