Abstract: Objective: To investigate the effects and safety of pemetrexed combined with gefitinib in the treatment of patients with advanced non-small-cell lung cancer( NSCLC) with second-line treatment of epidermal growth factor receptor-tyrosine kinase inhibitor ( EGFr-TKI) . Methods: Twenty-eight patients with stage Ⅲb /Ⅳ NSCLC treated with second-line treatment of EGFr-TKI( gefitinib /erlotinib) were treated with 500 mg /m2 of pemetrexed and 250 mg of gefitinib per day( 21 days each cycle) until these cases were improved. Results: The median follow-up time was 12. 4 months， except 1 case without evaluation， complete response in 0. 0%，partial response in 37. 0%， stabilization of the disease in 44. 4% and progression of disease in 18. 5% were found. The disease control and total effective rates were 81. 5% and 37. 0%， respectively. The time of median without disease progression and survival time were 7. 0 months and 13. 6 months， respectively. No tumor progression and survival rate of 1 year were 33. 3% and 55. 6%， respectively. The occurrence rate of skin rash with more grade Ⅲ was 14. 3%. Conclusions: The effects and tolerance of pemetrexed combined with gefitinib in the treatment of patients with advanced NSCLC with second-line treatment of EGFr-TKI are good.