This study was aimed to evaluate the efficacy and immunogenicity of combined hepatitis B vaccination with plasma-derived vaccine (PDV) and recombinant vaccine (RV). A total of 329 infants was recruited, including 224 high-risk infants born to hepatitis B e antigen-positive mothers and 105 low-risk infants born to hepatitis B e antigen-negative mothers. The high-risk infants received four doses of hepatitis B vaccine at 0, 1, 2 and 12 months of age with five different schedules. Group A1 and A2 infants were vaccinated with PDV as the first dose and RV (SB vaccine for group A1, MSD vaccine for group A2) as the remaining three doses. Group B1 and group B2 infants were vaccinated with PDV as the first two doses and RV (SB vaccine for group B1, MSD vaccine for group B2) as the remaining two doses. Group C infants received four doses of PDV. Low-risk infants were vaccinated with PDV at birth, and RV at 1 and 6 months of age (group D1, using SB vaccine; group D2, using MSD vaccine). At completion of vaccination schedules, 20 of 224 high-risk infants (9%) were positive for hepatitis B surface antigen. The overall protective efficacy was 90%. Hepatitis B surface antibody (anti-HBs)-positive rate ranged between 94 and 100% among the remaining infants. The protective efficacy and immunogenicity were similar among groups except that the mean level of anti-HBs in group C, D1 and D2 infants tended to be lower than that of the other four groups. To ensure an optimal immune response, four doses of vaccine are recommended in high-risk infants when two types of vaccine are to be used in combination.