Background: The presence of diabetes mellitus (DM) has been known as a poor prognostic factor in lung cancer and is associated with insulin-like growth factor 1 receptor (IGF-1R) over-expression. The IGF-1R pathway has a role in the acquisition of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of the present study is to determine the predictive role of DM to EGFR TKIs in NSCLC patients harboring sensitizing EGFR mutations. Methods: We retrospectively analyzed 68 recurrent or metastatic NSCLC patients who had activating EGFR mutations and received TKIs (gefitinib, erlotinib, afatinib). Comparison of progression free survival (PFS) according to the presence of DM was performed from all patients received EGFR-TKIs. Results: Of 68 EGFR-mutated patients, 14 (20.6%) had DM, 18 (26.5%) were male, and 65 (95.6%) had non-squamous histology. Among them, 52 (76.5%) received TKIs as the first-line treatment, and 54 (79.4%) patients were given gefitinib. There were no differences of clinicopathologic characteristics according to the presence of. Patients with DM showed significant shorter PFS (8.8 vs. 15.3 months, p=0.048) than those without DM from the patients received 1st line TKIs. Higher IGF-1R expression in tumor tissues by immunohistochemistry was observed from patients with DM. Conclusion: DM showed a negative predictive factor to the 1st-line EGFR TKIs in NSCLC patients harboring activating EGFR mutations. Further studies to overcome EGFR resistance in diabetic patients are clinically warranted regarding the IGF-1R pathways.