OBJECTIVES: Because young infants are at highest risk of pertussis complications, this study assessed whether neonatal acellular pertussis (aP) vaccination could provide earlier immunity. STUDY DESIGN: Neonates (n = 121) were randomly assigned (1:1) to receive either aP or hepatitis B vaccine (HBV) (controls) vaccine at birth, followed by vaccination with DTaP-HBV-IPV/Hib at 2, 4 and 6 months. Immune responses were measured. Reactogenicity was assessed for 7 days after each dose. RESULTS: The aP birth dose was followed by few adverse events. Reactogenicity of subsequent vaccine doses did not differ between groups. Seven serious adverse events were reported from each group; none were related to the study vaccines. At 3 months of age, vaccination with aP at birth had induced significantly higher antibody responses to the 3 pertussis antigens compared with controls. At 7 months, geometric mean/concentrations of antibodies against pertussis antigens were similar in both groups, and all subjects had reached "seroprotective" antibody concentrations against diphtheria, tetanus, and poliovirus types 1, 2, and 3. Geometric mean/concentrations of antibodies to haemophilus influenzae type b (Hib) and HBV were significantly lower in the aP group. CONCLUSIONS: Early neonatal immunization with aP was safe, well tolerated, and resulted in earlier antibody responses, seen after the first dose of a DTaP combination vaccine. Birth dose of aP did not induce immunologic tolerance to pertussis antigens but appear to dampen responses to Hib and HBV vaccines.