The aim of this study was to investigate the clinical efficacy and determine the prognostic value of Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) alone versus EGFR-TKIs plus chemotherapy for the treatment of advanced lung adenocarcinoma with EGFR Exon 19 Deletion(19Del), Exon 21 L858R (L858R) mutation. The demographic and clinical characteristics of 110 newly diagnosed metastatic lung adenocarcinoma patients with the EGFR 19Del, L858R mutation from June 2016 to October 2018 were retrospectively analyzed. Total remission rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and patient 1-year/2-year survival between EGFR-TKIs combined with first-line platinum-containing double-drug chemotherapy (Observation) group and an EGFR-TKIs alone (Control) group were evaluated and analyzed. For lung adenocarcinoma patients with the EGFR 19Del, L858R mutation, the Observation group had a better ORR (81.4% vs 52.2%), mPFS (12.0 vs 9 months), and 2-year survival (72.1% vs 52.2%) than the Control group, and the differences were statistically significant (P <.05), but DCR (95.3% vs 88.1%) and 1-year survival (90.7% vs 83.6%) were not significantly different between the groups (P> .05). For lung adenocarcinoma with the EGFR 19Del mutation, the Observation group showed a better ORR (81.8% vs 54.3%), and mPFS (14.5 vs 11.0 months) than the Control group, and the differences were statistically significant (P <.05), but DCR (95.5% vs 91.4%), 1-year survival (90.9% vs 85.7%), and 2-year survival (72.7% vs 60.0%) were not significantly different (P >.05). For lung adenocarcinoma with the EGFR L858R mutation, the Observation group showed a better ORR (81.0% vs 50.0%), mPFS (12.0 vs 9.0 months), and 2-year survival (71.4% vs 43.8%) than the Control group (P <.05), but DCR (95.2% vs 84.4%) and 1-year survival (90.5% vs 81.3%) were not significantly different (P >.05). Compared to EGFR-TKIs alone, EGFR-TKIs combined with chemotherapy improved ORR and mPFS in cases of advanced lung adenocarcinoma with EGFR 19Del, L858R mutation. In particular, patients with the EGFR L858R mutation showed a long-term survival benefit trend. EGFR-TKIs combined chemotherapy may therefore be a viable treatment method for delaying targeted drug resistance.