Objective <p>We aimed to evaluate the efficacy and safety of using/not using the antiviral drug tenofovir disoproxil fumarate (TDF) in preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) among pregnant women with high serum HBV DNA viral loads.</p> Methods <p>This retrospective study included 512 pregnant women with HBV infection and a high serum HBV DNA load (&gt; 2 × 10⁵ IU/mL) diagnosed and treated at our hospital between January 2018 and April 2023. Based on the treatment received, 314 women were identified as the TDF-treated group, while the remaining 198 comprised the TDF-unexposed group. All newborns received hepatitis B immune globulin and hepatitis B vaccine immediately after birth. Serum HBV DNA, HBsAg, HBeAg, total cholesterol (TC), and alanine aminotransferase (ALT) levels were compared before treatment and prior to delivery. The HBV infection rates of newborns (HBV DNA, HBsAg, HBeAg positivity), maternal adverse events, cesarean section rates, and pregnancy outcomes were also analyzed.</p> Results <p>Before delivery, serum HBV DNA, HBsAg, HBeAg, and ALT levels decreased in both groups, with significantly greater reductions in the TDF-treated group (<i>P</i> &lt; 0.05). No significant differences were observed in TC levels, adverse drug reactions, cesarean section rates, or adverse pregnancy outcomes (<i>P &gt;</i> 0.05). the HBV DNA, HBsAg, and HBeAg positivity rates of newborns were significantly lower in the TDF-treated group than those in the TDF-unexposed group (<i>P</i> &lt; 0.05). Neonatal body mass index, 1-min Apgar scores, and adverse neonatal outcomes did not differ significantly between groups (<i>P &gt;</i> 0.05).</p> Conclusion <p>TDF tablets can prevent MTCT of HBV in pregnant women with high HBV DNA loads. The treatment increases the seroconversion rates of HBV DNA, HBeAg, and HBsAg in mothers and infants, and shows a favorable safety profile without severe adverse outcomes.</p>