Summary. In infants born to hepatitis B surface antigen (HBsAg)–positive mothers, failure after passive–active immunization still occurs. The role of maternal hepatitis B DNA level and other risk factors in this setting remains unclear. This study retrospectively evaluated virologic and other risk factors associated with immunoprophylaxis failure in infants born to HBsAg-positive mothers. Between January 2007 and March 2010, we reviewed the clinical and virologic tests in 869 mother–infant pairs. All infants received the identical passive–active immunization schedule after birth. The failure infants (HBsAg positive at 7–12 months of age) were compared to infants who were HBsAg negative when tested during this time period. Among 869 infants, 27 (3.1%) infants were immunoprophylaxis failures and the other 842 (96.9%) infants remained HBsAg negative. When mothers’ pre-delivery HBV DNA levels were stratified to <6, 6–6.99, 7–7.99 and ≥8 log10 copies/mL, the corresponding rates of immunoprophylaxis failure were 0%, 3.2% (3/95), 6.7% (19/282) and 7.6% (5/66), respectively (P < 0.001 for the trend). All failure infants were born to hepatitis B e antigen (HBeAg)–positive mothers. Multivariate logistic regression analysis identified maternal HBV DNA levels [odds ratio (OR) = 1.88, 95% confidence interval (CI): 1.07–3.30] and detectable HBV DNA in the cord blood (OR = 39.67, 95% CI: 14.22–110.64) as independent risk factors for immunoprophylaxis failure. All failure infants were born to HBeAg-positive mothers with HBV DNA levels ≥6 log10 copies/mL. The presence of HBV DNA in cord blood predicted failure to passive–active immunization.