Objective · To evaluate the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in non small cell lung cancer (NSCLC) patients with uncommon EGFR 21L861Q mutation.  Methods · Between June 2011 and Marth 2015, clinical data of 21 stage Ⅲ B/ Ⅳ NSCLC patients who received EGFR-TKI harboring uncommon 21L861Q mutation in EGFR at the Shanghai Chest Hospital were collected. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS ) and overall survival (OS ) of the patients under TKI therapy were retrospectively analyzed.  Results · ORR and DCR of the patients under TKIs therapy (first-line+second-line+third-line) were 42.9% and 66.7% respectively. PFS and OS of patients who received therapy that consisted of EGFR-TKIs (first-line+second-line+third-line) were 7.03 months (95% CI, 5.50-8.69) and 22.80 months (95% CI, 16.22-25.65).  Conclusion · Our post-hoc analyses demonstrated that EGFR-TKIs showed activity in patients with uncommon EGFR 21L861Q-mutant NSCLC, less effective than in those with common mutations.