Epidermal growth factor (EGF) is an important factor for maintaining the esophageal functional integrity. Goettingen minipigs were treated with either placebo or subcutaneous EGF (30 micrograms/kg/day) for four weeks. Wistar rats were treated with either placebo or subcutaneous EGF (150 micrograms/kg/day) for four weeks. At sacrifice, esophageal samples were obtained for histology, immunochemistry, and lectin characterization. In pigs, the thickness of the esophageal epithelium was almost doubled in the EGF-treated animals. Characterization with lectins revealed a normal pattern of differentiation. Subcutaneously administered EGF was visualized on cells located basally in the esophageal epithelium. In rats, EGF-treatment increased the esophageal volume of the epithelium, the lamina propria of the mucosa, and the submucosa. In conclusion, systemic EGF challenge induces growth of the esophageal epithelium with an unaltered pattern of differentiation. This supports previous studies demonstrating a beneficial effects of systemic EGF-treatment on sclerotherapy-induced esophageal damage.