A whole-cell killed unencapsulated pneumococcal vaccine given by the intranasal route with cholera toxin as an adjuvant was tested in two animal models. This vaccination was highly effective in preventing nasopharyngeal colonization with an encapsulated serotype 6B strain in mice and also conferred protection against illness and death in rats inoculated intrathoracically with a highly encapsulated serotype 3 strain. When the serotype 3 challenge strain was incubated in the sera of immunized rats, it was no longer virulent in an infant-rat sepsis model, indicating that the intranasal immunization elicited protective systemic antibodies. These studies suggest that killed whole-cell unencapsulated pneumococci given intranasally with an adjuvant may provide multitypic protection against capsulated pneumococci.