IL-21 is a multifunctional cytokine, which influences many immune responses. To investigate its further functions in vivo, we have established IL-21 isoform transgenic mice (IL-21iso-Tg). Here we show a novel IL-21 function as an effect on neutrophil migration into duodenum, which augments systemic anaphylaxis. We found that immunized IL-21iso-Tg with ovalbumin (OVA) were more sensitive to OVA-induced systemic anaphylaxis with duodenal gross congestion than wild type mice. However, the titers of specific IgE or IgG against OVA in IL-21iso-Tg were not significantly higher than those in wild type mice. As a result of study to find the cause of the most striking change of the duodenum in IL-21iso-Tg, we found that the migrating neutrophils into duodenum were significantly increased before the immunization. These results suggested that migrated neutrophils in duodenum induced IgG-dependent anaphylaxis. As described in previous reports, gastrointestinal compartment constantly produces eotaxin, which regulates the baseline level of tissue eosinophils. So, we analyzed the expression of eotaxin receptor (CCR3, CD193) on neutrophils and eosinophils. CD193 expression on neutrophils in duodenum was upregulated in IL-21iso-Tg. The addition of IL-21 into bone marrow cell culture increased CD193+ neutrophils in vitro, and these cells were easily migrated into duodenum. These results revealed that IL-21 modified neutrophil differentiation and these neutrophils migrated into duodenum, which may endue the duodenum hypersensitivity in IL-21iso-Tg. Small intestine is hot spot to infection of parasite, such as hookworm, Cryptosporidium, Anisakis, or segmented worm. The early response of resident effector cells, mainly eosinophils and mast cells, are important to protect against the parasite infections before success of metabiosis. The CD193+ neutrophil subset, which is regulated by perturbation of neutrophil differentiation toward eosinophilic cells in chronic inflammatory condition involving IL-21, may assist with eosinophils and mast cells in small intestine.