Background and Aims: Growth hormone and insulin-like growth factor I (IGF-I) stimulate small bowel growth. The aim of this study was to analyze whether IGF-I mediates enterotrophic actions of growth hormone. Methods: IGF- I transgenic mice that overexpress an IGF-I transgene driven by the mouse metallothionein I promoter and are growth hormone deficient were compared with wild-type littermates. Growth of small bowel, abundance and localization of messenger RNAs for the IGF-I transgene, and insulin-like growth factor- binding protein 3 were assayed. Results: Small bowel length and mass were greater in IGF-I transgenic mice than in wild-type mice. Villus height, crypt depth, and crypt cell mitoses were greater in jejunum of transgenics than wild-type mice, but jejunal disacharidase activities were not increased. The transgene was expressed strongly in villus epithelial cells. Insulin-like growth factor-binding protein 3 messenger RNA was localized in the lamina propria. Regional expression of both correlated with the increase in mucosal mass. Conclusions: Effects of IGF-I overexpression on intestinal length and mucosal mass were similar to effects of growth hormone overexpression observed previously. Excess of IGF-I increased crypt cell proliferation, whereas excess of growth hormone did not increase crypt cell proliferation. IGF-I excess stimulated differentiation of intestinal epithelial cells less effectively than growth hormone excess.