While the pathophysiology of intestinal adaptation following small bowel resection (SBR) is not well understood, there is evidence to suggest an important role for epidermal growth factor (EGF) in this process. In waved-2 mice, a naturally occurring mutation results in reduced EGF receptor protein tyrosine kinase activity. We tested the hypothesis that an intact EGF receptor is essential for adaptation by subjecting this strain of mice to SBR. A 50% proximal SBR or sham operation (bowel transection with reanastomosis only) was performed in waved-2, heterozygous, and wild-type mice. After 3 days, adaptation was characterized in the remnant ileum as changes in DNA and protein content per unit length. Villus height and crypt depth were measured, and crypt cell proliferation rates were determined by the percentage of crypt cells taking up 5-bromodeoxyuridine. Following sham surgery, all mice regained their preoperative weight by the third postoperative day. After SBR, all mice gained weight while the waved-2 mice did not. Ileal DNA and protein significantly increased after SBR in wild- type and heterozygous mice while these parameters were unchanged in the waved-2 mice. Villus height and crypt cell proliferation increased in response to SBR in all groups; however, the changes were less pronounced in the waved-2 mice. Adaptation after SBR is impaired in waved-2 mice. Signal transduction by the EGF receptor is a critical component of this response. These data endorse a crucial role for EGF and its receptor in the pathogenesis of intestinal adaptation.