The usual primary endpoint in clinical trials for first-line chemotherapy in advanced non-small cell lung cancer is overall survival. Second-line chemotherapy can also prolong overall survival. Non-smoking history has been associated with a treatment effect for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) versus placebo for overall survival. We performed a retrospective analysis to identify prognostic factors for progression-free survival and overall survival in patients with advanced non-small cell lung cancer treated with first-line carboplatin/paclitaxel, and to examine the effect of second-line therapy on progression-free survival and overall survival. Ninety-eight patients (median age 61 years, 35 female, 74 adenocarcinoma, 68 smokers, 56 performance status 0) fulfilled our criteria, of which 75 patients (78%) received more than second-line therapy (docetaxel [54%] gefitinib [48%] erlotinib [4%]). For overall survival, smoking history and histology were significant prognostic factors. The 2-year overall survival rates were as follows: smokers, 17%; non-smokers, 52%, P < 0.0001; adenocarcinoma, 40%; other 15%, P = 0.0017. Multivariate analysis in patients who received second-line therapy showed treatment with EGFR-TKI was an independent predictor of overall survival. Smoking history and adenocarcinoma histology were prognostic factors for an improved outcome with carboplatin/paclitaxel in patients with non-small cell lung cancer. Our study results suggest that the use of EGFR-TKI after first-line treatment may be associated with an improvement in overall survival.