Background and objective Kirsten rat sarcoma viral oncogene (KARS) mutation is one of the major driver genes of non-small cell lung cancer (NSCLC). KARS is a resistant predictor of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), which raises controversy because of its role in chemotherapy sensitivity and prognosis. hTe aim of this study is to accumulate clinical experience in treating NSCLC patients harboringKARSmutation.MethodsA total of 107 NSCLC patients harboringKARSmutation were analyzed retrospectively. hTe effcacy was analyzed in terms of ifrst-line chemotherapy or EGFR-TKIs therapy.Results hTe objective response rate (ORR) to ifrst-line chemotherapy of 52 pa-tients with advanced disease harboringKARS mutation was 9.6%. hTe disease control rate (DCR) was 53.8%, and the median progression-free survival (PFS) was 3 months. hTe ORR to EGFR-TKIs therapy in 21 patients harboringKARS mutation and EGFR/KARS co-mutation was 9.5%; the DCR was 23.8%, and the median PFS was 1 month. hTe ORR and DCR to EGFR-TKIs therapy of patients withEGFR/KARS co-mutation were signiifcantly higher than those of patients withKARS mutation (50%vs 0,P=0.029; 75%vs 11.8%,P=0.043); the median PFS was also signiifcantly longer (3 monthsvs 1 month,P=0.004). Conclusion hTe effcacy to ifrst-line chemotherapy and EGFR-TKIs therapy in NSCLC patients harboringKARS mutation was poor; thus, new drugs should be developed. Furthermore, the existence ofEGFR/KARS co-mutation was conifrmed. Hence, EGFR-TKIs therapy should be administered to patients withEGFR/KARS co-mutation.