In a previous study, oral IGF-I at 65 nM increased lactase phlorizin hydrolase (LPH) activity and villus height in piglets, however, the mechanisms were unknown. Herein, the response to a range of doses of IGF-I was investigated and we hypothesized that LPH and villus height would respond to oral IGF-I in a dose-dependent manner. Two 14-d experiments were conducted using cesarean-derived piglets. In experiment 1, piglets (n ϭ 28) were fed formula containing 0, 33, 65, or 131 nmol/L (0, 0.25, 0.5, or 1.0 mg/L) recombinant human IGF-I. In experiment 2, 5Ј-bromodeoxyuridine was administered to piglets fed formula alone (n ϭ 4) or containing 131 nmol/L IGF-I (n ϭ 4). IGF-I did not affect body weight gain or intestinal weight or length. Jejunal villus height and LPH activity were significantly greater in piglets fed 131 nmol IGF-I/L than control piglets. Abbreviations AP-1, activator protein-1 BrdU, 5Ј-bromodeoxyuridine C/EBP, CCAAT/enhancer binding protein EF1-␣, elongation factor 1-␣ FLE, foremost labeled enterocyte HNF-1, hepatocyte nuclear factor-1 LPH, lactase phlorizin hydrolase BB LPH, brush border lactase phlorizin hydrolase proLPH h , high mannose lactase phlorizin hydrolase precursor proLPH c , complex glycosylated lactase phlorizin hydrolase precursor MAPK, mitogen activated protein kinase NHS, normal horse serum PI 3-kinase, phosphatidylinositol 3-kinaseThe presence of IGF-I in colostrum and milk (1) and IGF receptors within the intestine (2) has led to the postulate that milk-borne IGF-I could play a role in neonatal intestinal development (3). Our group and others have shown that orally administered IGF-I stimulates intestinal villus growth (4 -6) and LPH activity (E.C. 3.2.1.23-62) (6) in the neonatal piglet.However, the doses of IGF-I administered in these experiments (65-1300 nmol/L) were above the concentrations of IGF-I present in porcine colostrum (13-52 nmol/L) or mature milk (1.3-2.6 nmol/L) (7). It was unknown whether oral administration of lower doses of IGF-I would exert similar biologic effects within the neonatal intestine. Further, the mechanisms by which oral IGF-I up-regulated intestinal LPH activity and villus growth had not been described. Therefore, the goals of the current study were to determine the impact of a range of doses of oral IGF-I on intestinal villus growth and LPH activity and to investigate potential mechanisms underlying these ef-