Inhalational anthrax is the most severe form of anthrax. It has been shown in small-animal and non-human primate models that relatively large pools of ungerminated Bacillus anthracis spores can remain within the alveolar spaces for days to weeks post-inhalation or until transported to areas more favourable for germination and bacillary outgrowth. In this study, spores of the Ames strain that were exposed to germination-inducing media prior to intranasal delivery were significantly less infectious than spores delivered in either water or germination-inhibitory medium. The effect of manipulating the germination potential of these spores within the lungs of infected mice by exogenous germination-altering media was examined. The data suggested that neither inducing germination nor inhibiting germination of spores within the lungs protected mice from the ensuing infection. Germination-altering strategies could, instead, significantly increase the severity of disease in a mouse model of inhalational anthrax when implemented in vivo. It was shown that germination-altering strategies, in this study, were not beneficial to the infected host and are impractical as in vivo countermeasures.