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Objective The standard therapy aft er failure of the initial non-fi rst line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in advanced non-small cell lung cancer (NSCLC) has not yet been established. The aim of the current study was to identify whether the 2nd TKI treatment or chemotherapy (paclitaxel-containing or non-paclitaxel regimen) is the appropriate treatment for patients with NSCLC based on the effi cacy of the initial TKIs.Methods Seventy-two advanced NSCLC patients who had accepted 2nd TKIs or chemotherapy immediately afe er failure of the initial TKIs in non-fi rst line seing from May 1, 2004 to January 31, 2010 at the Sun Yat-sen University Cancer Center were enrolled. The primary endpoint [2nd progression-free survival (PFS)] and the second endpoint [overall survival (OS)] were compared among the 2nd TKI and chemotherapy groups as well as their subgroups.Results (1) Twenty-one patients were treated with 2nd TKIs, and 51 patients were administered chemotherapy aft er failure of the initial non-fi rst line TKI treatment. There was nonsignifi cant diff erence in the responses (P=0.900) [2nd PFS (P=0.833) and OS (P=0.369)]between the 2nd TKI and chemotherapy groups. (2) In the 2nd TKI group, 9 patients exhibited PFS≥7 months. The initial TKI treatment group exhibited a longer 2nd PFS than the other 12 patients with an initial PFS