Citrobacter rodentium, a natural mouse pathogen, belongs to the family of extracellular enteric pathogens that includes enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC). C. rodentium shares many virulence factors with EPEC and EHEC and relies on attaching-and-effacing lesion formation for colonization and infection of the gut. In vivo, C. rodentium infection is characterized by increased epithelial cell proliferation, mucosal thickening, and a TH1-type immune response, but with protective immunity believed to be mediated by serum immunoglobulin G (IgG). In this work, we characterize the immune response and pathology of mice lacking the p50 subunit of the transcription factor nuclear factor kappa B (NF-kappaB) during C. rodentium infection. We show that p50(-/-) mice are unable to clear C. rodentium infection. Furthermore, these animals show a reduced influx of immune cells into infected colonic tissue and greater levels of mucosal hyperplasia and the cytokines tumor necrosis factor alpha and gamma interferon. Surprisingly, despite being unable to eliminate infection, p50(-/-) mice showed markedly higher levels of anti-Citrobacter IgG and IgM, suggesting that antibody alone is not responsible for bacterial clearance. These data also demonstrate that non-NF-kappaB-dependent defenses are insufficient to control C. rodentium infection, and hence, the NF-kappaB p50 subunit is critical for defense against this noninvasive pathogen.