Angiogenin 4 (ANG4), a novel antimicrobial protein with multiple biological functions, such as antimicrobial, anti-inflammation, angiogenesis and regulating the body’s immune response, plays a key role in innate immunity. The expres-sion of ANG4 in neonatal mice intestine is regulated by some factors including microbial signal and developmental stage. Being an analogue of surface molecules of bacterial cell wall, chitosan oligosaccharide (COS) was selected as a inducer to explore the effects on ANG4 expression and mophology in post weaning mice intestine. qRT-PCR and Western blot analyses showed that the mRNA and protein levels of ANG4 increased suggesting that COS can upregulate the expression of ANG4. The results of HE staining of mouse intestinal tract showed that the height of intestinal villi, the depth of crypt and the value of V/C increased significantly. It indicates that COS can improve the integrity of intestinal mucosae in some extent through either inducing the expression of some intestinal antimicrobial proteins, such as ANG4, or its antimicrobial and immunomodulation activities, and provide the theoretical basis for the applications of COS and ANG4 in controlling the intestinal diseases in piglets. Key words: ANG4; COS; AMPs; qRT-PCR; Western blot