Signal‐transducing adaptor protein‐2 (STAP‐2) was cloned as a c‐fms/M‐CSF receptor interacting protein. STAP‐2 is an adaptor protein carrying pleckstrin homology and Src homology 2 like domains, as well as a YXXQ motif. STAP‐2 has been indicated to have an ability to bind and modulate a variety of signaling and transcriptional molecules. Especially, our previous in vitro studies showed that STAP‐2 is crucial for immune and/or inflammatory responses. Here, we have investigated the role of STAP‐2 in intestinal inflammation in vivo. The disruption of STAP‐2 attenuates dextran sodium sulfate induced colitis via inhibition of macrophage recruitment. To study whether hematopoietic or epithelial cell derived STAP‐2 is required for this phenomenon, we generated BM chimeric mice. STAP‐2‐deficient macrophages impair the ability of CXCL12‐induced migration. Intriguingly, STAP‐2 also regulates production of proinflammatory chemokines and cytokines such as CXCL1 and TNF‐α from intestinal epithelial cells. Therefore, STAP‐2 has a potential to regulate plural molecular events during pathological inflammatory responses. Furthermore, our findings not only indicate that STAP‐2 is important in regulating intestinal inflammation, but also provide new insights toward the development of novel therapeutic approaches.