Objective：This study compared prognoses of advanced non-small cell lung cancer patients with epidermal growth factor receptor exon 19 or 21 mutations after two types of first-line treatment：Icotinib hydrochloride alone or icotinib combined with chemotherapy. Methods：The clinical data of 174 patients admitted to the First Affiliated Hospital of Nanjing Medical University from August 2012 to October 2020 were retrospectively analyzed. Totally，82 cases carried EGFR 21 exon mutation，38 cases received first-line Icotinib therapy，while 44 cases received icotinib combined with the chemotherapy. 92 cases were with the presence of EGFR19 exon mutation，43 cases received first-line icotinib therapy，and 49 cases received iotinib combined with chemotherapy. We compared differences in objective response rate，disease control rate，progression-free survival，and overall survival between EGFR 21 and 19 exon mutation patients after receiving different treatment regimens. Results：Among the patients receiving icotinib treatment，the patients with EGFR21 mutation had a median PFS that was 3.5 months shorter than those with 19 mutation（9.5 months vs. 13.0 months，P=0.046）. There were no significant differences in the median OS，ORR and DCR after 1 cycle of treatment（P > 0.05）. Among patients receiving icotinib combined with chemotherapy，there was no significant difference in PFS，OS，ORR and DCR after 1 cycle of treatment in patients with EGFR exon 21 mutation compared to patients with EGFR exon 19 mutation（P > 0.05）. Among patients with EGFR 21 exon mutations，the median PFS was 5.8 months longer in the combination group compared to the single-agent group（15.3 months vs. 9.5 months，P=0.002）and the median OS was 20.2 months longer than in the single-agent group（46.0 months vs. 25.8 months，P=0.004）. There was no significant difference in ORR or DCR between the two groups after one cycle of treatment（P > 0.05）. Among patients with EGFR 19 exon mutations，median PFS was 9.1 months longer in the combination group compared to the single-agent group（22.1 months vs. 13.0 months，P < 0.001）and median OS was 35 months longer in the combination group compared to the single-agent group（61.0 months vs. 26.0 months，P < 0.001）. There was no significant difference in ORR and DCR between the two groups after one cycle of treatment（P > 0.05）. Conclusion：For patients with advanced NSCLC with EGFR-sensitive mutations，first-line treatment with icotinib combined with chemotherapy significantly improved PFS and OS compared with icotinib monotherapy. In particular，the PFS and OS in patients with EGFR 21 exon mutations were comparable to those in patients with EGFR 19 exon mutations.