Introduction: Thymoma and thymic carcinoma (TC) are neoplastic diseases with reported chemosensitivity to a broad range of agents. However, because of the rarity of these diseases, few prospective trials have been conducted in patients with advanced thymic malignancies. We conducted a prospective phase II trial to evaluate the clinical activity of pemetrexed, a multitargeted antifolate agent, in previously treated patients with thymoma and TC. Methods: A total of 27 previously treated patients (16 with thymoma and 11 with TC) with advanced, unresectable disease were treated with pemetrexed, 500 mg/m2, intravenously every 3 weeks for a maximum of six cycles or until undue toxicity or progressive disease. All patients received folic acid, vitamin B12, and steroid prophylaxis. Results: The median number of cycles administered was 6 (range 1–6). Nine patients with a total of 14 events had grade 3 toxicities; no grade 4 toxicities were noted. In 26 fully evaluable patients, two complete and three partial responses (according to the Response Evaluation Criteria in Solid Tumors) were documented (all in patients with stage IVA thymoma, except for one partial response with stage IVA TC). A total of 14 patients completed the full six cycles of treatment, 7 patients progressed while undergoing therapy, 5 patients discontinued therapy because of intolerance, and 1 patient discontinued therapy because of progressive Morvan syndrome. The median progression-free survival time for all patients was 10.6 months (12.1 months for those with thymoma versus 2.9 months for those with TC). With 23 deaths at data cutoff, the median overall survival time was 28.7 months (46.4 months for those with thymoma versus 9.8 months for those with TC). Conclusions: Pemetrexed is an active agent in this heavily pretreated population of patients with recurrent thymic malignancies, especially thymoma.