Haemophilus influenzae organisms elaborating one of six capsular polysaccharides (types a-f) colonize the respiratory tract of humans, but only type b strains commonly cause systemic infections. To investigate the role of capsular polysaccharides as virulence determinants, rats were inoculated with capsulated (types a-f) or noncapsulated clinical isolates or with laboratory-derived type b and type d transformants of a noncapsulated strain. After intraperitoneal inoculation, all capsulated strains possessed the potential for systemic infection, but type b strains were more virulent; noncapsulated strains were noninvasive. After intranasal inoculation, only type b strains were invasive. There was no difference in efficiency of nasopharyngeal colonization between type b and type d transformants. After intravenous inoculation, only type b strains resulted in persistent bacteremia. Thus, type b strains--clinical isolates or transformants--display unique virulence characteristics. These data suggest that elaboration of type b capsule is necessary and sufficient for this virulence of H. influenzae type b in the rat.