Abstract The inflammasome cytokine IL-1b is an important mediator of the inflammatory responses against invading pathogens. However, it is not clear whether sustained IL-1b signaling following the loss of its endogenous inhibitor, secretory IL-1 receptor antagonist (sIL-1Ra), could improve mucosal immunity against the enteropathogen, Citrobacter rodentium (CR). In light of increased prescription of rec-sIL-1Ra (aka Anakinra) to treat inflammatory bowel disease, we undertook this study. At basal levels, sIL-1Ra-deficient (sIL-1RaKO) mice displayed leukocytosis and elevated inflammatory marker, i.e. serum and fecal lipocalin 2. Furthermore, bone marrow-derived macrophages and neutrophils from sIL-1RaKO mice generated higher levels of iNOS and nitrite, and ROS and NETs, respectively. These results collectively suggest sIL-1RaKO mice have low-grade chronic inflammation. Based on these results, we hypothesized that sIL-1RaKO mice with persistent IL1-b signaling could efficiently clear CR infection than their WT littermates. Oral challenge of CR (1×109 CFU/mouse) resulted in luminal colonization, which peaked at day 7 post-infection, in both groups; however, sIL-1RaKO mice displayed a higher CR burden and an exacerbated infection. The aggravated course of infection was further visualized by inoculating sIL-1RaKO mice with bioluminescent CR. Histologic analysis revealed that transmissible colonic hyperplasia was more pronounced in sIL-1RaKO mice. Interestingly, basal ileal Paneth’s cell-specific antimicrobial proteins (Ang4 and Reg3g) were significantly reduced in sIL-1RaKO mice. Collectively, our results demonstrate that a balanced mucosal IL-1b signaling is required to counter and clear enteropathogen infection.