Infection with pathogenic microbes often results in a significant inflammatory response. A cascade of proinflammatory cytokines including tumor necrosis factor α (TNF-α) and IL-1 initiates this response. Although there is a clear role for IL-1 during infection, little is known to distinguish the role of IL-1α from that of IL-1β during this process. With the use of Yersinia enterocolitica as a model enteric pathogen, we have identified a specific role for IL-1α in inducing pathologic inflammation during bacterial infection. Depletion of IL-1α in mice infected with wild-type Y. enterocolitica results in significantly decreased intestinal inflammation. Furthermore, a bacterial mutant that does not induce IL-1α expression but induces normal levels of IL-1β, TNF-α, and IFN-γ, causes greatly reduced intestinal inflammation and is attenuated by LD50 analysis in the C57BL/6 mouse model. These results demonstrate a distinct and unrecognized role for IL-1α in inducing intestinal inflammation that cannot be compensated for by the endogenous levels of IL-1β, TNF-α, or IFN-γ that are produced in response to Y. enterocolitica. Additionally, these results suggest that IL-1α-induced inflammation is a major contributor to the pathology of yersiniosis.