A family of human and animal pathogens, including enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC), trigger formation of 'attaching and effacing' lesions on cultured and intestinal epithelial surfaces. However, our understanding of these events in vivo is incomplete. To further study these interactions in a natural infection model, weaned rabbits were infected with rabbit enteropathogenic E. coli O103 (REPEC O103), followed clinically, and infected tissues were evaluated by electron and light microscopy. Of the 36 rabbits challenged, morbidity and mortality were 65 and 23%, respectively. Twenty-four hours after infection, expression of fimbriae-like organelles was observed on the bacterial surface. Microvilli of ileal Peyer's patches (PP) became disorganized, and intestinal mucus secretion increased which coincided with intraluminal binding of the pathogen in the proximal colon. Forty-eight hours after infection, there was conspicuous lack of fimbriae-like organelle expression, while bacterial adherence preferentially occurred at the domed villi of PP. Seventy-two hours after infection, broad morphological heterogeneity was noted within pedestals beneath attached bacteria, including extended pseudopods. We conclude that REPEC O103 express surface organelles during initial exposure to the host, that the initial target sites of adherence are the domed villi of ileal PP, and that increased mucus secretion occurs during REPEC O103 infection. As well, extended pseudopod formation was demonstrated in vivo.