Two theories have been proposed to account for the mucosal injury associated with intestinal ischemia, hypoxia-countercurrent exchange, and oxygen free radicals. The countercurrent mechanism suggests that mucosal injury should occur predominately during the ischemic period, whereas the oxygen free radical hypothesis predicts that the majority of mucosal injury results from reperfusion of ischemic tissue. Histological specimens obtained during the ischemic period and following reperfusion allowed a systematic evaluation of the time course of development of mucosal lesions in a regional ischemia model. Reperfusion after 3 h of regional hypotension reduced mean mucosal thickness from 1,022.2 ± 6.3 to 503.6 ± 10.0 μm. The decrease in mucosal thickness was largely due to a reduction in villus height, inasmuch as the reduction in crypt depth was statistically insignificant. A significantly smaller change in mucosal thickness was observed when the bowel was subjected to 3 h ischemia without reperfusion. The mucosal injury produced by 3 h ischemia and 1 h reperfusion was more severe than that produced by 4 h ischemia without reperfusion. The results of this study suggest that most of the tissue damage produced by the widely employed regional hypotension model occurs at the time of reperfusion.