Dogs were evaluated as experimental models for the study of diarrheal disease produced by enterotoxigenic Escherichia coli. Although a suitable whole model for orogastric bacterial challenge could not be developed, chronic jejunal Thiry-Vella loops were used to study the secretory effects of multiple jejunal challenges with enterotoxin of either Vibrio cholerae or E. coli. The heat-stable and heat-labile E. coli enterotoxins could be differentiated clearly in this model. Sequential weekly challenges over a four-week period showed a significant decrease in loop secretory response to homologous enterotoxin, although levels of antitoxin in serum remained unchanged, a finding suggesting a local immune response. Dogs challenged with E. coli enterotoxin were markedly protected against subsequent challenge with V. cholerae enterotoxin; the converse was not true. Histologic studies of the loops showed only minimal atrophy, and results of absorption studies in the loops were normal. These studies suggest that mongrel dogs are resistant to colonization by enterotoxigenic E. coli and partially resistant to challenge with enterotoxin, perhaps on an immune basis due to prior antigenic exposure. Multiple challenges with enterotoxin effect a decreased secretory response; this finding also suggests a local immune mechanism.