Growth hormone (GH) and insulin-like growth factor-I (IGF-I) play important roles in wound healing during intestinal injury and inflammation, but there is also indirect evidence that locally expressed IGF-I may act to induce excessive collagen deposition, which can lead to intestinal fibrosis. Factors that dictate the balance between normal wound healing and excessive healing responses are unknown. Using RNase protection assay and in situ hybridization, we determined if GH and/or IGF-I increase type I collagen deposition in the intestine of rats fed by total parenteral nutrition (TPN), a feeding modality used for many patients following intestinal surgery and resection. We also used an in vitro model system to confirm our in vivo effects and directly evaluate the relative potency of GH and IGF-I on DNA synthesis and collagen deposition in intestinal myofibroblasts. Both GH and IGF-I stimulated collagen production in vivo and in vitro and IGF-I, but not GH, stimulated DNA synthesis in vitro. In collagen production, GH was less potent than IGF-I. Suppressors of cytokine signaling (SOCS) are cytokine inducible proteins that negatively feedback to inhibit the actions of cytokines and we recently found that GH selectively upregulates SOCS-2 in the intestine of TPN-fed rats. We examined whether SOCS-2 may be responsible for the difference in magnitude of action of GH and IGF-I on collagen accumulation. GH, but not IGF-I, induced SOCS-2 in isolated myofibroblasts and overexpression of SOCS-2 led to a suppression of GH- and IGF-I-induced collagen accumulation. SOCS-2 null mice infused with IGF-I showed greater collagen gene expression compared with WT mice. Myofibroblasts isolated from SOCS-2 null mice showed increased IGF-I-stimulated DNA synthesis compared with WT cells. Taken together, these findings suggest that SOCS-induced by GH may play an important role in suppressing collagen accumulation and mesenchymal cell proliferation induced by GH or GH-induced IGF-I, providing a mechanism for the differing potencies of GH and IGF-I on intestinal mesenchyme and collagen synthesis.