A new study published in PLoS One compared virulence properties of the neonatal Escherichia coli (E. coli) bacteremia clinical isolate SCB34 with the archetypal neonatal E. coli meningitis strain RS218. Here, whole-genome sequencing data was used to compare the protein coding sequences among these clinical isolates and 33 other representative E. coli strains. The results showed that oral inoculation of newborn animals with either strain produced septicemia; in contrast, intraperitoneal injection caused septicemia only in pups infected with RS218 but not in those injected with SCB34. Apart from being virulent only through the oral route, SCB34 demonstrated significantly greater invasion and transcytosis of polarized intestinal epithelial cells in vitro, as compared to RS218. Furthermore, protein coding sequences comparisons underlined the presence of known virulence factors that are shared among several of these isolates, and disclosed the existence of proteins exclusively encoded in SCB34 – many of which remain uncharacterized. Thus, this study demonstrated that oral acquisition is detrimental for the virulence properties of the neonatal bacteremia clinical isolate SCB34. It was speculated that this characteristic, along with its enhanced ability to invade and transcytose intestinal epithelium are determined by specific virulence factors that predominate in this strain.