Escherichia coli strains that cause disease outside the intestine are known as extraintestinal pathogenic E. coli (ExPEC) and include human uropathogenic E. coli (UPEC) and avian pathogenic E. coli (APEC). Regardless of host of origin, ExPEC strains share many traits. It has been suggested that these commonalities may enable APEC to cause disease in humans. Here, we begin to test the hypothesis that certain APEC strains possess potential to cause human urinary tract infection through virulence genotyping of 1,000 APEC and UPEC strains, generation of the first complete genomic sequence of an APEC (APEC O1:K1:H7) strain, and comparison of this genome to all available human ExPEC genomic sequences. The genomes of APEC O1 and three human UPEC strains were found to be remarkably similar, with only 4.5% of APEC O1's genome not found in other sequenced ExPEC genomes. Also, use of multilocus sequence typing showed that some of the sequenced human ExPEC strains were more like APEC O1 than other human ExPEC strains. This work provides evidence that at least some human and avian ExPEC strains are highly similar to one another, and it supports the possibility that a food-borne link between some APEC and UPEC strains exists. Future studies are necessary to assess the ability of APEC to overcome the hurdles necessary for such a food-borne transmission, and epidemiological studies are required to confirm that such a phenomenon actually occurs.Escherichia coli is among the world's most well-studied organisms and is often found at the forefront of advancing technology. Not surprisingly, E. coli is on the leading edge of an ongoing shift in the field of genomics (3,6,65). Now that at least one representative organism per species has been sequenced for most pathogens of interest, the focus in genomics has reoriented towards obtaining multiple sequences within a species. With more genomic sequences available for E. coli than for any other species, it leads this trend (3). Thus far, all of the pathogenic E. coli strains sequenced have originated from human hosts (6,8,10,24,47,68). This bias has left a gap in our knowledge, as various E. coli strains cause significant and widespread disease in animals, including in those raised for human consumption (2, 13, 41). Consequently, while the genomic analysis of E. coli strains from animals can be justified solely on the basis of E. coli's detrimental impact on animal agriculture, a broader justification would also include the potential link between animal-source E. coli and human disease.Links between human and animal disease caused by E. coli are well established in some instances but remain speculative in others. For instance, recent reports of outbreaks of human urinary tract infections (UTIs) have stimulated interest in the potential that E. coli from animals has to cause human UTIs via the food supply (28,41,49). Since UTIs are among the world's most common bacterial infections (20), cause significant morbidity, and cost the health care system of the United States over a billion dolla...