Background & Aims: Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that's associated with intestinal adaptation following resection. Herein we investigate the effects of GLP-2 in a total parenteral nutrition (TPN) supported model of experimental short bowel syndrome (SBS). Methods: Juvenile SD rats underwent a 90 % small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: Enteral diet and i.v. saline infusion; TPN only; or TPN + 10 µg/kg/hr GLP-2 . Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized and intestinal tissue processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. Results: TPN + GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability when compared to the TPN alone animals (P<0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression (P<0.01) compared to either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indices compared with non-treated animals. Conclusions: This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indices of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.