Escherichia coli O157:H7 is a food-borne pathogen that can cause hemorrhagic colitis and, occasionally, hemolytic uremic syndrome, a sequela of infection that can result in renal failure and death. Here we sought to model the pathogenesis of orally-administered E. coli O157:H7 in BALB/c mice with an intact intestinal flora. First, we defined the optimal dose that permitted sustained fecal shedding of E. coli O157:H7 over 7 days ( approximately 10(9) colony forming units). Next, we monitored the load of E. coli O157:H7 in intestinal sections over time and observed that the cecum was consistently the tissue with the highest E. coli O157:H7 recovery. We then followed the expression of two key E. coli O157:H7 virulence factors, the adhesin intimin and Shiga toxin type 2, and detected both proteins early in infection when bacterial burdens were highest. Additionally, we noted that during infection, animals lost weight and approximately 30% died. Moribund animals also exhibited elevated levels of blood urea nitrogen, and, on necropsy, showed evidence of renal tubular damage. We conclude that conventional mice inoculated orally with high doses of E. coli O157:H7 can be used to model both intestinal colonization and subsequent development of certain extraintestinal manifestations of E. coli O157:H7 disease.