Prior studies of intestinal adaptation following massive small bowel resection (SBR) have focused on growth factors and their effects on amplification of the gut mucosa. Since adaptive changes have also been described in intestinal smooth muscle, we sought to determine the effect of targeted smooth muscle growth factor overexpression on resection-induced intestinal adaptation. Male transgenic mice with smooth muscle cell overexpression of insulin-like growth factor-I (IGF-1) by virtue of an -smooth muscle actin promoter were obtained. SMP8 IGF-1 transgenic (IGF-1 TG) and non-transgenic littermates (NT) underwent 50% proximal SBR or sham operation and were then sacrificed after 3 or 28 days. NT mice showed the expected alterations in mucosal adaptive parameters after SBR such as increased wet weight and villus height. The IGF -I TG mice had inherently taller villi, which did not increase significantly after SBR. In addition, IGF-1 TG mice had a 50% postresection persistent increase in remnant intestinal length, which was associated with an early decline and later increase in relative mucosal surface area. These results indicate that growth factor overexpression within the muscularis layer of the bowel wall induces significant postresection adaptive intestinal lengthening and a unique mucosal response. IGF-1 signaling within the muscle wall may play an important role in the pathogenesis of resection-induced adaptation.