Small-bowel resection leads to hyperplasia of the residual small intestine, However, the factors initiating small-bowel hyperplasia are not clearly understood, although oral intake either by direct contact with the small bowel or via hormonal or neurovascular factors has been suggested as the major stimulus. In order to determine whether oral intake is an obligatory prerequisite for small-intestinal hyperplasia, we compared rats one week after undergoing a 70-cm proximal intestinal resection with sham-operated animals. Resected, orally fed rats demonstrated small-intestinal hyperplasia, whereas resected and sham-operated intravenously alimented rats did not. There were no differences in gut weight, mucosal weight, mucosal protein, or DNA between resected or sham-operated intravenously alimented rats. These data provide direct experimental proof that oral intake is a necessary stimulus for small-intestinal hyperplasia after resection.