BACKGROUND: We investigated the effects of variations in the postresection timing of glucagon-like peptide-2 (GLP-2) administration on intestinal morphology and activity. METHODS: A rat model of 90% intestinal resection (SBR) with exclusively parenteral nutritional (TPN) was used. Early versus late postresection GLP-2 stimulation was compared between SBR + TPN alone, SBR + TPN + GLP-2 (first wk), and SBR + TPN + GLP-2 (second wk) (n = 8/group). On d 14, animals were sacrificed and remnant ileum analyzed for morphology, crypt cell proliferation index (CPI), apoptosis index (API), and nutrient transporter expression (SGLT-1, GLUT-2, GLUT-5). In a separate study, the resection-induced effect on acute GLP-2 responsiveness was studied at d 3 and 10, in control or SBR animals, both supported with TPN. (n = 6). RESULTS: Bowel length, weight, and width were increased in SBR + TPN + GLP-2 (first wk) compared with the SBR + TPN alone and SBR + TPN + GLP-2 (second wk) groups. Animal weight, villus height, total mucosal surface area, and CPI increased in both GLP-2 treated groups compared with the SBR + TPN group. Villus height and crypt depth effects were most pronounced in the SBR + TPN + GLP-2 (second wk) group. Increased expression of mRNA for the GLP-2 receptor was noted at d 3, declining below baseline by d 10, however this was not correlated with GLP-2 activation of enteric neurons. Exogenous GLP-2 increased the activation of submucosal neurons at d 3 in controls; resected animals had a higher baseline activity, but exogenous GLP-2 did not activate this further at either d 3 or 10 postresection. CONCLUSIONS: GLP-2 effects on intestinal growth are maximal in the early postresection period and are associated with an apparent increase in expression of the receptor but no increase in neuronal activation. This suggests that the intestinal adaptive and growth promoting actions of GLP-2 may be mediated by non-neuronal effector pathways. Although further studies are required, early treatment with GLP-2 following resection may maximize intestinal growth.