ABSTRACTPreclinical ResearchHuman adrenomedullin (hAM), a hypotensive peptide, also has anti‐inflammatory effects. hAM can reduce the severity of the dextran sulphate sodium (DSS)‐ and 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in animal models. Furthermore, in a clinical study, hAM treatment reduced the Disease Activity Index in ulcerative colitis. However, these therapeutic effects required continuous administration of hAM as the half‐life of native hAM is quite short in blood. To resolve this problem, hAM N‐terminal was conjugated with two kinds of polyethylene glycol (PEG); 5 kDa PEG or 60 kDa PEG (5 kDa PEG‐hAM and 60 kDa PEG‐hAM respectively). In a previous study, 5 kDa PEG‐hAM stimulated cAMP production and prolonged the plasma half‐life compared with native hAM. Herein we examine the effect of PEG‐hAM in the DSS colitis model. Treatment with both PEG‐hAM preparations reduced the total inflammation score. In addition, the plasma half‐life of 60 kDa PEG‐hAM was much longer than 5 kDa PEG‐hAM. In summary, a single subcutaneous administration of 60 kDa PEG‐hAM reduced the total inflammation score in mice with DSS‐induced colitis. Therefore, these results suggest that 60 kDa PEG‐hAM is a possible therapeutic agent for the treatment of inflammatory bowel disease. Drug Dev Res 78 : 129‐134, 2017. © 2017 Wiley Periodicals, Inc.