Technical Abstract: Citrobacter rodentium is a mouse pathogen that shares many characteristics with human enteropathogenic (EPEC) and enterohemorrhagic (EHEC) Escherichia coli, the causative agents for human disease, and serves as a useful model to study immunity to these organisms. In this study, the effect of a double deficiency in selenium and vitamin E on the pathogenesis of a C. rodentium infection was evaluated. Mice fed a selenium and vitamin E deficient diet for 6 weeks had increased colon and spleen bacterial loads, increased crypt hyperplasia and influx of infiltrating cells, and gross changes to crypt architecture, including ulceration, denuding of the epithelial layer, and increased granuloma formation. Cytokine and chemokine mRNA levels were measured by real-time PCR. Cytokine expression was down-regulated on day 7 in infected mice fed the deficient diet, compared to infected mice fed the control diet, but the two groups were comparable on day 12. There was also an increase in MCP-1 expression in infected deficient mice on day 12, but not on day 7. Production of antigen-specific IgM and IgG antibodies was not affected by the deficiency. The results indicate that selenium and vitamin E play an important role in the host’s resistance to the pathological effects of a C. rodentium infection that mimics many aspects of human disease caused by common food-borne pathogens.