Background: This study analyzed the negative prognostic factors in patients who received second-line chemotherapy for advanced inoperable non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed the records of 137 patients with inoperable stage III-IV NSCLC who received second-line chemotherapy. The effects of clinical parameters on survival were analyzed and the hazard ratios (HR) for mortality were identified by a Cox regression analysis. Results: Sex, age older than 65 years, smoking history, cell type, T-stage, best response to first-line chemotherapy and first-line chemotherapy regimen were significant negative predictors in univariate analysis. The multivariate analysis showed that patients older than 65 years (HR, 1.530; 95% confidence interval [CI], 1.020-2.297), advanced T stage (T4 vs. T1; HR, 2.273; 95% CI, 1.010-5.114) and non-responders who showed progression with first-line chemotherapy (HR, 1.530; 95% CI, 1.063-2.203) had higher HR for death. Conclusion: The age factor, T stage and responsiveness to first-line chemotherapy were important factors in predicting the outcome of patients with advanced NSCLC who received second-line chemotherapy. The results may help to predict outcomes for these patients in the future.