Objective: To further observe the efficacy and safety of pemetrexed, combined with Irinotecan or oxaliplatin or cisplatin in treating patients with advanced gastric cancer as second-line or third-line chemotherapy. Methods: From September 2013 to February 2014 we recruited 50 patients with advanced gastric cancer, with stage IV disease or postoperative recurrence, or unresectable. Then treated with pemetrexed based chemotherapy. After two cycles of treatment, efficacy and toxicity were evaluated. Results: Pemetrexed based chemotherapy was used as second-line in 33 patients, RR(CR+PR) is 41.2%. And achieved 36.4% when used as third-line. Overall response rate of 50 patients treated with Pemetrexed based treatment was 38% (CR+PR). Treatment related side effects were bone marrow suppression, vomiting, hepatic dysfunction and malaise.No treatment related death occurred. Conclusions: Treatment with pemetrexed based chemotherapy is active and is well tolerated in patients with advanced gastric cancer.