BALB/c and C57BL/6 mice were challenged by aerosol or intradermally with low doses ( approximately 10-20 colony forming units) of virulent type A and type B strains of the facultative intracellular pathogen, Francisella tularensis, and the course of infection was monitored. Both mouse strains were equally susceptible to infection, but type A strains reached lethal numbers a few days earlier than type B strains regardless of challenge route. BALB/c mice showed overt signs of infection for several days, whereas C57BL/6 mice remained asymptomatic until a few hours before death. Histological changes were extensive and severe in the liver and spleen, but much more limited in the lungs, even in mice challenged by aerosol. Thus, it appears that regardless of the route of infection, systemic rather than pulmonary infection was the likely cause of death following low dose challenge with virulent F. tularensis.