A standard, valid assay of comorbidities for elderly patients with advanced non-small-cell lung cancer (NSCLC) who have received antitumor therapy is needed to provide useful prognostic information. The aim of this study was to analyze prognostic factors and validate classic Charlson comorbidity index (CCI) and comorbidity scores in elderly patients with advanced NSCLC treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). A retrospective analysis was conducted on 162 patients with advanced NSCLC over 70 years old at diagnosis, who were treated with cytotoxic chemotherapy or with EGFR-TKIs between April 2003 and April 2009 at Kyoto University Hospital. Collected data included clinical assessments, treatments, toxicities, and outcomes. Survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated with log-rank and Cox regression tests. Based on multivariate analysis, unspecified NSCLC histology [Hazard ratio (HR), 1.631; 95% Confidence interval (CI), 1.184-2.263; P = 0.0016], more than 3 comorbidities (HR, 1.317; 95% CI, 1.020-2.675; P = 0.0350), and a CCI of more than 3 (HR, 1.321; 95% CI, 1.031-1.664; P = 0.0285) were significant independent negative prognostic factors for survival. Our results indicate that CCI and the number of comorbidities are independent predictors of survival in elderly patients undergoing systemic chemotherapy including EGFR-TKIs for advanced NSCLC. These factors should be taken into consideration in the pretreatment assessment as important factors predicting survival outcome.