Background and purpose: New treatment methods should be explored for non-small cell lung cancer (NSCLC) patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). This study compared the curative effect of pemetrexed with gefitinib or pemetrexed alone in advanced NSCLC with acquired resistance to EGFR-TKI. Methods: This study included 62 NSCLC pa

tients with advanced EGFR gene mutation and acquired resistance to EGFR-TKI. Among those

32 patients were treated with pemetrexed and gefitinib

and 30 patients treated with gefitinib alone. The differences in outcomes between the two strategies were assessed. Results: Objective response rate (ORR) was 46.9% for those treated with pemetrexed and gefitinib and 20% for those treated with pemetrexed alone(χ

2

=4.933

P0.05). There was no significant differences between the two groups on disease control rate (DCR) (P0.05). The median progression-free survival (PFS) was 8.0 months on pemetrexed and gefitinib group and 6.3 months on pemetrexed alone (χ

2

=8.063

P0.05). There was no significant differences between the two groups on overall survival (OS) (P0.05). Higher occurrence of leukocytopenia and rash was observed in the pemetrexed and gefitinib group than in the pemetrexed group (P0.05). There was no significant differences between the two groups on grade 3-4 toxicities (P0.05). Conclusion: This study was to demonstrate that continuation of EGFR-TKI with pemetrexed in patients with acquired resistance improves outcomes compared with pemetrexed alone. An improved response rate and PFS were observed in this study. A larger prospective clinical trial is needed to  further evaluate this promising strategy.