Epidermal growth factor (EGF) protects gastric mucosa against many injurious factors, but no study has examined whether EGF may protect against ischemia-reperfusion (I-R)-induced gastric mucosal injury. We assessed the effect of EGF pretreatment on the extent of ischemia-reperfusion-induced gastric mucosal damage in rats. Assessment of injury and protection included: the extent of macroscopic necrosis; qualitative and quantitative histology with measurement of deep mucosal necrosis; microvascular permeability after injection of fluorescein-conjugated albumin; and transmission electron microscopy. After I-R, saline-pretreated rats (placebo group) had macroscopic necrosis involving 40 +/- 6% of total gastric mucosal area. Histology revealed exfoliation of the surface epithelial cells, mucosal hemorrhages, microvascular injury, and extensive deep mucosal necrosis involving 7 +/- 5% of mucosal strips. Microvascular permeability assessed by fluorescein-conjugated albumin was significantly increased to 327 +/- 29% of that in normal rats (without ischemia-reperfusion). Transmission electron microscopy showed severe microvascular injury. EGF pretreatment significantly reduced gross mucosal necrosis to 17 +/- 6% and deep histologic mucosal necrosis to 2 +/- 1% (both p < 0.01 versus saline pretreated). Integrity of the mucosal microvessels was preserved and microvascular permeability was close to normal. This study demonstrates that EGF significantly reduces ischemia-reperfusion injury to the rat gastric mucosa and that this effect of EGF may be mediated by its protection of the mucosal microvessels.