Ischemia/reperfusion (I/R) injury to the intestinal mucosa occurs in several commonly encountered clinical situations, such as necrotizing enterocolitis and nonocclusive mesenteric insufficiency. No clinically feasible technique is available for mucosal preservation during ischemia. The goal of this work was to determine whether the continuous intraluminal flow of oxygenated perfluorocarbon (PFC) could protect mucosal integrity and function in a rat model of intestinal I/R injury. Rats were subjected to ischemia by clipping the superior mesenteric artery (SMA) for 60 minutes. Reperfusion was achieved by release of the clip for 120 minutes. Animals were divided into 4 groups: Sham (laparotomy alone), I/R (I/R alone), I + PFC/R (PFC was administered during the ischemic interval only), I/R + PFC (PFC was delivered only during reperfusion). Tissue sections were examined blindly to assess mucosal integrity, and mucosal dissacharidase activities were measured to assess function. Oxygenated PFC, when administered during ischemia alone, ameliorated I/R-induced mucosal injury; however, when it was delivered during reperfusion alone, the mucosal injury worsened. When oxygenated PFC was administered throughout I/R, the degree of mucosal injury was similar to the I + PFC/R group, and dissacharidase activities were preserved when compared with the I/R group. Intraluminal perfusion of oxygenated PFC during ischemia preserves mucosal function and integrity, and may offer a new treatment modality for a variety of mesenteric ischemic disorders.