Abstract: Objective To investigate the clinical efficacy and toxicity of icotinib and gefitinib in advanced lung adenocarcinoma with EGFR mutation. Methods Clinical data about 56 patients with advanced lung adenocarcinoma admitted to our hospital from January 2012 to June 2014 were retrospectively analyzed. They were divided into icotinib group and gefitinib group randomly, and patients in icotinib group were treated with icotinib three times a day by 125 mg, patients in gefitinib group were treated with gefitinib once a day by 250 mg at least one month. Results In icotinib group, complete response (CR), partial response (PR), stable disease and progressive disease were achieved in 0, 11, 7 and 10 patients, respectively, with the objective response rate (ORR) of 39.3% and disease control rate (DCR) of 64.3%. In gefitinib group, complete response (CR), partial response (PR), stable disease and progressive disease were achieved in 0, 7, 8 and 13 patients, respectively, with the objective response rate (ORR) of 25% and disease control rate (DCR) of 53.6%. There was no significant difference between the two groups in ORR, DCR, TTP and OS. The main adverse reactions were rash and diarrhea, which were less occurred in icotinib group (P< 0.05). Conclusion Icotinib and gefitinib have similar efficacy in advanced lung adenocarcinoma with EGFR mutation, however, the toxicity of icotinib is better tolerated and acceptable.