Abstract: Objective To observe the efficacy and safety of pulsatile administration of highdose gefitinib or erlotinib for advanced nonsmall cell lung cancer（NSCLC） patients with secondary drug resistance to standard dose of epidermal growth factor receptor tyrosine kinase inhibitor（EGFR-TKI） treatment. Methods Forty-two cases of NSCLC patients with drug resistance after 1year conventional treatment of gefitinib or erlotinib were recruited in this study from August 2013 to December 2014. The gefitinib group， including 29 cases， received one dose of 1000 mg gefitinib every four days. The erlotinib group， including 13 cases， received one dose of 450 mg erlotinib every three days. Treatments continued till disease progression or development of intolerable toxicity. The shortterm efficacy and progressionfree survival（PFS） were compared between the two groups. Results The median PFS of the total 42 cases was 30 months， with 31 months in gefitinib group and 24 months in erlotinib group， respectively. No significant difference was observed in the two groups in PFS（P＞0.05）. After the highdose pulsatile administration， the total group had 8 cases of PR， 11 cases of SD and 23 case of PD. Meanwhile， the response rate（RR） was 19.0％， the disease control rate（DCR） was 45.2％，the median PFS was 6 months. Gefitinib group had 6 cases of PR， 9 cases of SD and 14 cases of PD. The erlotinib group had 2 cases of PR， 2 cases of SD and 9 cases of PD. The median PFS of gefitinib and erlotinib group was 8 months and 6 months， respectively， with no significant difference（P＞0.05）. All cases were divided to 2 groups based on the mutation of EGFR exon. Exon 19 mutation group had 4 cases of PR， 6 cases of SD and 17 cases of PD. Exon 21 mutation group had 4 cases of PR， 5 cases of SD and 6 cases of PD. The median PFS of two groups were 6 months and 7 months， respectively， with no significant difference（P＞0.05）. Adverse reactions were all in grade 12， such as rash， fatigue， anorexia and dry skin were observed. The incidence had no difference between the two groups（P＞0.05）. Conclusion For advanced NSCLC patients who have previously undergone a standard dose treatment of gefitinib or erlotinib， highdose EGFR-TKI pulsatile treatment is a safe and efficient choice， which can improve prognosis of a portion of the patients.