Systemically primed BALB/c mice developed severe diarrhea after repeated oral administration of ovalbumin (OVA). Histological analysis demonstrated that dramatic infiltration of eosinophils and mast cells occurred in the large intestine but not in the small intestine of mice with diarrhea. Interestingly, CD4(+) alphabeta T cells of the large intestine secreted IL-4 and IL-13 at high levels. Identically treated STAT6 gene-disrupted mice failed to develop OVA-induced diarrhea. Further, treatment of BALB/c mice with monoclonal anti-IL-4 antibody prevented the development of allergic diarrhea. An adoptive transfer study showed that systemically primed splenic CD4(+) T cells were preferentially recruited into the large intestine upon exposure to oral OVA. These results strongly suggest that systemically derived CD4(+) alphabeta T cells of the large intestine play a critical role in the onset of Th2-mediated intestinal allergic disorders via STAT6 signal transduction.