Abstract: Objective To evaluate the efficacy of increasing dose of gefitinib or erlotinib after gefitinib failure in the treatment for advanced non-small cell lung cancer with resistance to routine dose of gefitnib. Methods A total of 40 patients with non-small cell lung cancer with resistance to routine dose of gefitinib after treatment for more than 6 months in The First Affiliated Hospital of Dalian Medical University from June 2007 to May 2012 were enrolled. They were equally randomized into two groups, one group treated with increasing dose of gefitinib, and the other group treated with erlotinib. The clinical efficacy and incidence of adverse reaction were comparatively analyzed. Results The efficacies of increasing dose of gefitinib group and erlotinib after gefitinib failure group were CR 0 vs. 0 case, PR 2 vs. 0 case, SD 11 vs. 13 cases, PD 7 vs. 7 cases. And the median progression free survival (PFS) were 9.1 and 3.0 months, respectively(P<0.05). The most common toxic effects were skin rash and diarrhea. Univariate and multivariate analysis revealed that increasing dose of geftinib or erlotinib after gefitinib failure were the independent prognosis factors. Conclusion Both increasing dose of gefitinib and erlotinib after gefitinib failure can be effective treatments for advanced non-small cell lung cancer to gefitnib responders, but the median PFS was significant prolonged by increasing dose of gefitinib, which appears more informative than replacement therapy with erlotinib in prognosis.