The role of type I interferon (IFN-αβ) in modulating innate or adaptive immune responses against mycobacterial infection in the lung is unclear. In this study we investigated the susceptibility of IFN-αβ-receptor-deficient (IFN-αβR−/−) mice to pulmonary infection with aerosolized Mycobacterium bovis bacillus Calmette–Guérin (BCG). During early infection (2–3 weeks), enhanced growth of BCG was measured in the lungs of IFN-αβR−/− mice compared to wild-type mice. However, during late infection the burden of BCG was similar in the lungs of IFN-αβR−/− and wild-type mice. Although control of BCG growth was delayed, recruitment and activation of T and natural killer cells, production of IFN-γ, and cytokine expression were all similar in wild-type and IFN-αβR−/− mice. However, decreased expression of nitric oxide in bronchoalveolar lavage fluids from IFN-αβR−/− mice correlated with enhanced growth of BCG. Bone marrow-derived macrophages from IFN-αβR−/− mice also produced less nitric oxide following infection with BCG in vitro. These findings suggest that IFN-αβ contributes to innate immunity to pulmonary mycobacterial infection by augmenting production of nitric oxide.