Type I interferons (IFN-alpha and IFN-beta) are important for protection against many viral infections, whereas type II interferon (IFN-gamma) is essential for host defense against some bacterial and parasitic pathogens. Study of IFN responses in human leprosy revealed an inverse correlation between IFN-beta and IFN-gamma gene expression programs. IFN-gamma and its downstream vitamin D-dependent antimicrobial genes were preferentially expressed in self-healing tuberculoid lesions and mediated antimicrobial activity against the pathogen Mycobacterium leprae in vitro. In contrast, IFN-beta and its downstream genes, including interleukin-10 (IL-10), were induced in monocytes by M. leprae in vitro and preferentially expressed in disseminated and progressive lepromatous lesions. The IFN-gamma-induced macrophage vitamin D-dependent antimicrobial peptide response was inhibited by IFN-beta and by IL-10, suggesting that the differential production of IFNs contributes to protection versus pathogenesis in some human bacterial infections.