Immunization with the B oligomer of pertussis toxin protected neonatal mice from a lethal respiratory challenge with Bordetella pertussis. All mice immunized with 8 micrograms of B oligomer survived aerosol challenge and had peripheral leukocyte counts and weight gains similar to those of mice immunized with pertussis toxoid before challenge and to those of control mice that were not challenged. Unprotected mice challenged with an aerosol of B. pertussis had an increase in peripheral leukocyte count, failed to gain weight, and died within 21 days of challenge. Protection appeared to be dose dependent, since a dose of 1 microgram of B oligomer per mouse prevented death in 100% of the mice challenged with B. pertussis, whereas 0.4 micrograms of B oligomer protected 50% of the challenged mice. Mice immunized with the B oligomer had increases in immunoglobulin G (IgG) anti-B oligomer in sera and in IgG and IgA anti-B oligomer in bronchoalveolar lavage fluids 1 to 3 weeks after respiratory challenge. Specific anti-B oligomer antibodies could not be detected in unimmunized, infected mice at the same time after challenge. Intravenous administration of the monoclonal antibody 170C4, which binds to the S3 subunit of the B oligomer, protected neonatal mice from B. pertussis respiratory challenge, while administration of an IgG1 anti-tetanus toxin monoclonal antibody, 18.1.7, was not protective. We conclude that anti-B-oligomer-mediated neutralization of pertussis toxin is one mechanism of protection in the mouse model of B. pertussis aerosol challenge.