IL-1α and IL-1β are potent inflammatory cytokines and important mediators of immune responses to intracellular pathogens such as Mycobacterium tuberculosis (Mtb). Here, we investigated the role of IL-1α and IL-1β during chronic Mtb infection and spontaneous reactivation in mice. For long-term neutralization of IL-1α, IL-1β or both, mice were immunized with virus-like particles (VLPs) displaying either of the cytokines, inducing strong and long-lasting neutralizing IgG responses. Blocking of IL-1α but not of IL-1β resulted in increased susceptibility to chronic infection with Mtb. Neutralizing either IL-1α or IL-1β alone did not lead to increased reactivation of latent tuberculosis. The generation of antibodies neutralizing both IL-1α and IL-1β simultaneously, did not influence weight gain during Mtb reactivation and the slight increase in pulmonary bacillary counts were not significant when compared to control-immunized group. Thus, the results suggest that IL-1α is the major mediator of the IL-1RI-dependent and protective innate immune responses to Mtb in mice.