Objective The brain is the main site of failure in cancer patients with epidermal growth factor receptor (EGFR) mutations undergoing treatment. However, identifying patients who may develop brain metastases (BM) is difficult. Autophagy is critical for cancer initiation and progression. We hypothesized that genetic variants in autophagy core genes might contribute to BM risk of non-small cell lung cancer (NSCLC) following treatment with EGFR tyrosine kinase inhibitor (EGFR-TKIs).Methods We systematically examined 16 potentially functional genetic polymorphisms in seven autophagy core genes among 105 TKI-treated NSCLC patients. Kaplan-Meier curves were plotted to assess the cumulative BM probability. Univariate and multivariate Cox proportional hazard regression analyses were utilized to calculate hazard ratios (HRs) and 95％ confidence intervals (CIs). We evaluated the potential associations of these genes with subsequent BM development. Results We found that ATG16L1: rs2241880, ATG10: rs10036653, rs3734114, and ATG3: rs7652377 are significantly associated with NSCLC treated with EGFR-TKIs (all P < 0.05). BM developed more often in patients with ATG3 rs7652377 CC genotype (33％), ATG10 rs10036653 AA genotype (43％), ATG10: rs3734114 CT/CC genotype (46％), and ATG16L1 rs2241880 AA genotype (37％) compared to patients with AA genotypes at rs7652377 (12％), AT/TT genotypes at rs10036653 (16％), the TT genotype at rs3734114 (13％), or AG/GG genotypes at rs2241880 (17％). Conclusion These associations may be critical for understanding the role of autophagy in BM risk. Future prospective studies are needed to determine if prophylactic cranial irradiation (PCI) could offer a survival benefit in this group of patients.