Several growth factors are trophic for the gastrointestinal tract and able to reduce the degree of intestinal damage caused by cytotoxic agents. However, studies of epidermal growth factor (EGF) for chemotherapy-induced intestinal injury are conflicting. The recent development of a transgenic mouse that specifically overexpresses EGF in the small intestine provided a unique opportunity to assess the contribution of this growth factor in mucositis. After a course of fluorouracil, the transgenic mice fared no better than control mice. Their weight recovery was inferior, and their mucosal architecture was not preserved. Apoptosis was not decreased and proliferation was not increased in their crypts. To corroborate the negative findings in the transgenic mice, ICR mice were treated with exogenous EGF after receiving fluorouracil. These mice were not protected from intestinal damage, despite the ileal upregulation of native and activated EGF receptor in these animals. Furthermore, no benefits were observed with alternate doses, schedules, or routes of administration of EGF. Finally, mucositis was induced in mutant mice with specific defects of the EGF signaling axis. When compared to control mice, clinical and histological parameters of intestinal injury after fluorouracil were no different in waved-2 mice, which possess functionally diminished EGF receptors, or waved-1 mice, which lack transforming growth factor . These findings do not support a critical role for EGF or its receptor in chemotherapy-induced intestinal injury.