Peptidylarginine deiminase (PAD) is an enzyme, which citrullinates arginine residues of proteins, and is involved in extracellular traps (ETs). ETs are phenomenon in which histones and granulocyte proteins are released from neutrophils and macrophages into the extracellular space with DNA, and are associated with the pathogenesis of various inflammatory diseases. PAD4 is expressed mainly in neutrophils and contributes to ETs in neutrophils while PAD2 is widely expressed including macrophages. We recently showed that PAD4-derived ETs plays a detrimental role in TNBS-induced colitis. In the present study, we investigated the role of ETs derived from PAD2 and PAD4 in DSS-induced colitis. Colitis was induced in male mice lacking PAD2 (PAD2KO) and PAD4 (PAD4KO) mice by DSS solution for 7 days. DSS treatment caused severe colitis accompanied by weight loss, diarrhea, and bloody stool. Further, increase in MPO activity and inflammatory cytokine expression as well as induction of ETs were observed. The severity of colitis with increase in MPO activity and cytokine expression was significantly exacerbated in either PAD2KO or PAD4KO mice compared with wild-type (WT) mice. In particular, rectal bleeding were typically observed in these KO mice. These findings suggest that PAD2 and PAD4 play the protective role in DSS-induced colitis. Thus, PAD2 and PAD4 may have a different involvement in the pathogenesis of DSS- and TNBS-induced colitis.