In 1984, a growth factor was identified that stimulated hepatocyte DNA synthesis. This growth factor, referred to as hepatocyte growth factor (HGF), has been shown to enhance growth of intestinal epithelial cells in vitro. Recently, we reported that HGF can increase absorption and intestinal mass when given systemically in an in vivo model. This study was designed to examine if luminally administrated HGF can stimulate intestinal epithelial cell mass and function. Twenty-five young adult Sprague-Dawley rats had catheters inserted into the small intestine and connected to subcutaneously placed osmotic minipumps. The rats were divided into five groups (n = 5 for each group) based on the contents in the osmotic pump: group 1 received normal saline (control); groups 2, 3, 4, and 5 received HGF in increasing doses of 30, 75, 150, and 300 microg/kg/day, respectively. Following a 14-day infusion, [14C]galactose and [14C]glycine absorption was measured in 10-cm segments of mid-small intestine using an in vivo closed-recirculation technique. Mucosal DNA content and protein content of the same small bowel segment were determined for each group. HGF significantly increased galactose absorption at doses of 75 (P < 0.01) and 150 (P < 0.05) microg/kg/day and glycine absorption at doses of 30 (P < 0.05) and 75 (P < 0.01) microg/kg/day. HGF significantly increased DNA content (P < 0.01) at each dose and protein content when given at 30 (P < 0.01) and 75 (P < 0.01) microg/kg/ day. These data demonstrate that luminal administration of HGF can increase intestinal epithelial cell mass and function in vivo. HGF may be clinically useful in patients with inadequate intestinal function.