Objective: To investigate the association between single nucleotide polymorphisms (SNPs) of rs3130542 and rs4821116 in the HLA-C and UBE2L3 genes and the effect of telbivudine antiviral therapy during pregnancy in HBeAg-positive mothers through a large-sample control study, and to provide a basis for the development of individualized blocking strategies for pregnant women with a high viral load. Methods: The genotypes of rs3130542 and rs4821116 were determined for 312 pregnant women with a high viral load who received telbivudine antiviral therapy during the second or third trimester of pregnancy, and the dominant model, recessive model, and additive model were used to analyze the association between the genotypes of these two loci and the reduction in HBV DNA load. The Shapiro-Wilk test and the Levene test were used to evaluate data normality and homogeneity of variances, and the t-test or the non-parametric Mann-Whitney U test was selected based on data type and was used for the comparison of means between groups. The Hardy-Weinberg equilibrium was used to determine the genotype of SNPs, and the dominant model, recessive model, and additive model were used for analysis. Results: Mothers with an AA/AG genotype of rs3130542 in the HLA-C gene had a significantly higher probability of HBV DNA load ≥10³ IU/ml at the time of delivery (P < 0.05) and a significantly higher risk of failure in the prevention of mother-to-child transmission, no matter whether they started to take telbivudine at week 24 or 28 of pregnancy. The association between the genotype of rs4821116 in the UBE2L3 gene and the reduction in viral load in pregnant women needed to be confirmed by studies with a larger sample size. Conclusion Pregnant women with a high viral load and an AA/AG genotype of rs3130542 in the HLA-C gene tend to have poor response to antiviral therapy during pregnancy, and early antiviral intervention is recommended for such patients.