The role of salivary epidermal growth factor (EGF) in wound healing of the tongue was studied in mice. Sialoadenectomy (removal of the submandibular glands, which are the major source of salivary EGF) or sham operation was performed 2 wk before infliction of wound on the tongue. Salivary EGF levels were 1.98 +/- 0.47 and 0.20 +/- 0.04 (SE) microgram/ml in sham-operated male and female mice, respectively, whereas sialoadenectomy reduced salivary EGF to undetectable levels in both male and female mice. A circular superficial wound measuring approximately 2 mm in diameter was made in the middle of the tongue by mechanically ablating only the epithelial layer. The rate of wound healing was monitored by a stereomicroscopy. Sialoadenectomized male mice showed a significant delay in wound healing compared with sham-operated controls. Treatment of sialoadenectomized male mice with EGF (1 microgram/ml in drinking water) restored the rate of wound healing to normal levels. Transforming growth factor (1 microgram/ml) was as effective as EGF in the promotion of wound healing, whereas nerve growth factor (1 microgram/ml) was ineffective. Essentially the same results were obtained in female mice. In addition, two classes of EGF binding sites with high and low affinity were demonstrated in the epithelium of the tongue obtained from male and female mice. The maximum binding sites and dissociation constants of the EGF receptors were the same between males and females and were not affected by sialoadenectomy. These results suggest that salivary EGF is involved in the promotion of wound healing of the tongue in both male and female mice.