The bacterium Mycobacterium tuberculosis (Mtb) causes tuberculosis and is responsible for more human mortality than any other single pathogen. Progression to active disease occurs in only a fraction of infected individuals and is predicted by an elevated type I interferon (IFN) response^{, , , , –}. Whether or how IFNs mediate susceptibility to Mtb has been difficult to study due to a lack of suitable mouse models^{, , , , –}. Here, we examined B6.Sst1^S congenic mice that carry the ‘susceptible’ allele of the Sst1 locus that results in exacerbated Mtb disease^{, –}. We found that enhanced production of type I IFNs was responsible for the susceptibility of B6.Sst1^S mice to Mtb. Type I IFNs affect the expression of hundreds of genes, several of which have previously been implicated in susceptibility to bacterial infections^{,,, , –}. Nevertheless, we found that heterozygous deficiency in just a single IFN target gene, Il1rn, which encodes interleukin-1 receptor antagonist (IL-1Ra), is sufficient to reverse IFN-driven susceptibility to Mtb in B6.Sst1^S mice. In addition, antibody-mediated neutralization of IL-1Ra provided therapeutic benefit to Mtb-infected B6.Sst1^S mice. Our results illustrate the value of the B6.Sst1^S mouse to model IFN-driven susceptibility to Mtb, and demonstrate that IL-1Ra is an important mediator of type I IFN-driven susceptibility to Mtb infections in vivo.