Although much is understood regarding the role of B7/CD28 family of costimulatory molecules in regulating host resistance in the context of several pathogens, analogous information with Mycobacterium tuberculosis is lacking. To address the requirements of B7-mediated costimulation in host resistance against tuberculosis, mice deficient in both B7.1 and B7.2 (B7DKO) were aerosol infected with M. tuberculosis Erdman and disease progression was monitored. We report herein that B7DKO mice are initially able to contain the bacterial load in the lung, but exhibit enhanced susceptibility during chronic infection. Despite the early control of bacterial replication, B7DKO mice essentially start off with compromised Th1 immunity and slower granulomatous response in the lung, characterized by markedly reduced lymphocytic infiltration. As the infection progresses from acute phase to the chronic phase, the nascent granulomas in the B7DKO lungs never fully achieve the architecture of granulomas developing in wild-type mice. Instead, lesions spread progressively to involve much of the lung in the B7DKO mice, ultimately leading to necrosis. Thus, early control of M. tuberculosis growth in the lung can occur in the absence of B7 costimulation and is less dependent on Th1 immunity and formation of a granulomatous structure. However, B7 costimulation is critical for long-term containment of infection within lung granulomas. These findings suggest that the use of costimulation-based immunomodulators may have significant repercussions on the induction of host protective immunity against tuberculosis.