Abstract Tenofovir alafenamide fumarate (TAF) has been endorsed by guidelines for blockade of mother-to-child transmission of hepatitis B virus (HBV), given that its efficacy and safety are comparable to tenofovir disoproxil fumarate (TDF). However, there is a lack of comparative studies regarding the treatment efficacy in patients with diverse viral loads. This study retrospectively analyzed 96 hepatitis B e antigen (HBeAg)-positive pregnant women with HBV DNA levels ≥2 × 105 IU/mL. Based on viral loads (HBV DNA levels), participants in the TAF and TDF groups were stratified into three subgroups, namely the High-G (titer ≥8 log10 IU/mL), Middle-G (7 log10 IU/mL ≤ titer <8 log10 IU/mL) and Low-G (titer <7 log10 IU/mL) subgroups. The primary endpoint was effectiveness of TAF and TDF in patients with varying viral loads, while secondary endpoints were hepatitis B surface antigen (HBsAg) positivity in infants at 7 -12 months and the safety profile for mothers and children. Compared to baseline levels, median HBV DNA levels in mothers were decreased by 4.51 and 4.09 log10 IU/mL in the TAF and TDF groups (P = 0.04) pre-delivery, respectively. In the High-G subgroup, the titers were significantly lower in the TAF group (P = 0.045), a higher proportion of patients experienced a virus decline of ≥4 log10 IU/mLin the TAF group compared with the TDF group, with rates of 78.26% versus 58% (P = 0.034), respectively. Moreover, the median serum phosphate levels significantly decreased from baseline to pre-delivery in the TDF group (P = 0.04). Finally, infants in both cohorts tested negative for HBsAg at 7-12 months after delivery. Overall, our findings indicated that TAF can be considered the preferred option for treatment of HBeAg-positive pregnant women with HBV DNA levels ≥8 log10 IU/mL.