The pathology of Crohn's disease and ulcerative colitis is characterized by chronic inflammation and destruction of the gastrointestinal epithelium. Although suppression of inflammatory mediators remains the principle component of current disease therapeutics, strategies for enhancing repair and regeneration of the compromised intestinal epithelium have not been widely explored. The demonstration that a peptide hormone secreted by the intestinal epithelium, glucagon-like peptide-2 (GLP-2), is a potent endogenous stimulator of intestinal epithelial proliferation in the small bowel prompted studies of the therapeutic efficacy of GLP-2 in CD1 and BALB/c mice with dextran sulfate (DS)-induced colitis. We report here that a human GLP-2 analog (h[Gly2]GLP-2) significantly reverses weight loss, reduces interleukin-1 expression, and increases colon length, crypt depth, and both mucosal area and integrity in the colon of mice with acute DS colitis. The effects of h[Gly2]GLP-2 in the colon are mediated in part via enhanced stimulation of mucosal epithelial cell proliferation. These observations suggest that exploitation of the normal mechanisms used to regulate intestinal proliferation may be a useful adjunct for healing mucosal epithelium in the presence of active intestinal inflammation.