Whole cell pertussis vaccine made from wild-type strains of Bordetella pertussis protect mice against intracerebral (IC) challenge with virulent strain. Similar vaccines made from strains that do not produce pertussis toxin (Ptx) do not protect. These Ptx deficient strains were either naturally occurring Phase III cultures or cultures developed by modifying the gene responsible for Ptx production. Nanogram doses of Ptx added to vaccines made from Ptx-deficient cells converted them into highly efficient vaccines for the protection of mice to IC challenge. Purified surface antigens of B. pertussis such as filamentous hemagglutinin which do not protect mice to IC challenge with B. pertussis were also made effective when nanogram doses of Ptx were added. The doses of Ptx did not develop detectable antibodies to itself. Two actions of Ptx are possibly involved in this protection-inducing effect. One is its ability to stimulate antibodies specially of the IgE class, and the other is its ability to counteract the action of epinephrine responsible for preventing increases in capillary permeability. When Ptx was given to mice 4 hours to 4 days prior to an antiserum directed to surface antigens of B. pertussis it also was able to increase the protective activity of the antisera. This action is probably mainly due to the non-specific effect of Ptx which inhibits and protects the permeability-neutralizing action of epinephrine.