Objective To evaluate the association of TERT gene polymorphisms with short-term efficacy and safety of lenvatinib in advanced hepatocelluer carcinoma.Methods The gene expression data and clinical data of hepatocelluer carcinoma were downloaded from the TCGA database. R software package was used to analyze the difference of TERT expression and its correlation with patient’s prognosis. A total of 124 cases with pathologically confirmed at the Affiliated Hospital from December 2018 to August 2022 were collected which received lenvatinib and all of them with complete data. 3 mL of peripheral venous blood sample was obtained from each patient before therapy, then single nucleotide polymorphism of rs10069690 and rs2853669 was conducted using high throughout sequencing technology, the relationship among the genotypes with therapeutic short-term efficacy and safety was analyzed.Results 106 patients could be evaluated for curative effect, among which 44 patients were PR and 62 patients were SD/PD. The most common any-grade adverse events were hypertension, hand-foot syndrome, diarrhoea, proteinuria, decreased appetite, fatigue and the incidence were 29.2%, 20.8%, 19.8%, 21.7%, 39.6%, 44.3% respectively. The polymorphism of rs10069690 were related with the therapeutic response(P=0.024), compared with C allele, individuals with T allele had a higher therapeutic response (OR=2.250, 95%CI:1.103~4.591). The polymorphisms of rs10069690 and rs2853669 were not statistically related with the adverse reactions. Conclusion Patients with hepatocelluer carcinoma who carries the rs10069690 T allele have better efficacy when treated with lenvatinib