The objective of this study was to directly study a role for mast cells in ischemia-reperfusion (I/R)-induced mucosal and microvascular dysfunction. I/R was induced in the intestine and skeletal muscle (gastrocnemius and cremaster muscle) of wild-type mice and mast cell-deficient mice (W/Wv). Changes in mucosal permeability (blood-to-lumen clearance of 51Cr-EDTA), leukocyte infiltration (myeloperoxidase activity in the intestine and intravital microscopy in the cremaster muscle), and vascular permeability (tissue wet-to-dry weight ratio and FITC-albumin leakage) were measured as indexes of tissue dysfunction. In wild-type animals, intestinal I/R induced a significant increase in mucosal permeability, leukocyte infiltration, and vascular permeability. Mast cell-deficient animals were completely protected from I/R-induced mucosal dysfunction. However, skeletal muscle I/R induced a significant increase in leukocyte infiltration, FITC-albumin leakage, and edema formation to the same degree in both wild-type and mast cell-deficient animals. These data suggest that mast cells may be important mediators of I/R-induced mucosal and microvascular dysfunction in the intestine but not of microvascular dysfunction in skeletal muscle.