Abstract: Objective To explore the effect of gemcitabine （GEM） plus S-1 （GS） regime as a second-line therapy in aged patients with stage ⅢB nonoperative squamous cell lung cancer. Methods The clinical data of these eligible patients was collected from November 2009 to September 2014. A total of 105 patients were randomized divided into GS group and GEM group. Response to chemotherapy was assessed by RECIST criteria 1.1 and toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria 4.0. The clinical followup data from chemotherapy were investigated. The factors influencing the prognosis of the patients with Cox risk proportional regression model. Results All 105 patients were evaluable for recent efficacy and safety. The response rate and the disease control rate were 39.62% （21/53） and 49.06% （26/53） in GS group， higher than 19.23% （10/52） and 26.92% （14/52） of GEM group （P<0.05）. The median progressionfree survival and overall survival were 4.3 months and 9.2 months in the GS group， better than 3.8 months and 8.0 months in the GEM group （P<0.05）. Compared with GEM group， the incidences of white blood cell decrease， nausea and vomiting， diarrhea， constipation， abdominal pain， mouth ulcers， skin rash and fatigue were significantly higher in GS group than in GEM group （P<0.05）. TNM stage and development time were the independent factors affecting the overall survival by multiple factor analysis. Conclusion The GS regimen is more benifitial than the GEM monotherapy regimen as the secondline therapy in treating elder patients with squamous cell lung cancer in improving the efficacy and prognosis. The adverse reactions were more serious in GS regimen， which should be used in specific patients with better physical health due to its potential serious adverse events.