Background: Platinum-hased chemotherapy for advanced non-small cell lung cancer (NSCLC) is still considered the first choice, presenting a modest survival advantage. However, the patients eventually experience disease progression and require second-line therapy. While there are reliable predictors to identify patients receiving first-line chemotherapy, very little knowledge is available about the prognostic factors in patients who receive second-line treatments. The present study was therefore performed. Methods: We retrospectively reviewed 107 patients receiving second-line treatments from August 2002 to March 2012 in the Dicle University, School of Medicine, Department of Medical Oncology. Fourteen potential prognostic variables were chosen for analysis in this study. Univariate and multivariate analyses were conducted to identify prognostic factors associated with survival. Result: The results of univariate analysis for overall survival (OS) were identified to have prognostic significance: performance status (PS), stage, response to first-line chemotherapy response to second-line chemotherapy and number of metastasis. PS, diabetes mellitus (DM), response to first-line chemotherapy and response to second-line chemotherapy were identified to have prognostic significance for progression-free survival (PFS). Multivariate analysis showed that PS, response to first-line chemotherapy and response to second-line chemotherapy were considered independent prognostic factors for OS. Furthermore, PS and response to second-line chemotherapy were considered independent prognostic factors for PFS. Conclusion: In conclusion, PS, response to first and second-line chemotherapy were identified as important prognostic factors for OS in advanced NSCLC patients who were undergoing second-line palliative treatment. Furthermore, PS and response to second-line chemotherapy were considered independent prognostic factors for PFS. It may be concluded that these findings may facilitate pretreatment prediction of survival and can be used for selecting patients for the correct choice of treatment.