Abstract Background: Epidermal Growth Factor Receptor (EGFR) tyrosine-kinase inhibitors (TKIs) have changed treatment strategies for patients with advanced non-small-cell lung cancer (NSCLC) harbouring mutations in EGFR gene. This retrospective analysis assessed efficacy and safety of TKIs in elderly compared to younger patients. Patients and methods: 49 patients with advanced NSCLC and mutations in exon 19 or 21 receiving a first-line therapy with TKIs were included and divided into patients aged <70 years and patients aged ≥ 70 years. Primary endpoints were progression free survival (PFS), response rate (RR) and clinical benefit in terms of quality of life; secondary endpoint was overall survival (OS). Results: Median PFS was significantly longer in elderly in comparison to younger patients (12.6 and 5.6 months, respectively; p= .008). RR was 64% in younger patients and 75% in elderly population. Eighteen out of 20(90%) elderly patients treated with gefitinib experienced symptoms relief and upgrading of performance status. No difference in terms of OS was found (p= .34). Conclusion: TKIs seem more effective in elderly than in younger patients affected by NSCLC with an EGFR gene mutation. We hypothesize that the main difference between the two populations is the number of medications related to concomitant comorbidities that cause an increased plasma level of TKIs.