The domestic pig shares many similarities with humans in anatomy, physiology, and immunology. As such it is an attractive animal model to study human tuberculosis (TB). In this study, we examined disease outcome in pigs challenged via two different routes with either the human TB bacillus Mycobacterium tuberculosis Erdman (M. tb) or bovine TB bacillus M. bovis AF2122/97 in head-to-head comparisons. Pigs challenged intravenously with M. bovis exhibited greater morbidity and rapid onset of mortality, higher bacterial burden and tissue necrosis compared to pigs challenged similarly with M. tb. Concordantly, pigs challenged with aerosolized M. bovis exhibited reduced weight gain and more severe pathology than pigs challenged similarly with M. tb. Specifically, M. bovis challenged pigs presented a spectrum of granulomatous lung lesions similar to that in human TB. In contrast, pigs challenged with M. tb presented mostly early-stage granulomas. Irrespective of challenge dose and pathology however, peripheral IFN-γ responses were similar in both M. bovis and M. tb aerosol challenged pigs. Although M. bovis appears to be more virulent than M. tb, both can be used to model different facets of human TB in pigs, depending on whether one seeks to recapitulate active or latent forms of the disease.