Ischaemia reperfusion (IR) injury is a serious complication of cardiovascular disease, transplantation and replantation surgery. Once established there is no effective method of treatment. Although studies using mast cell-depleted (Wf/Wf) mice implicate mast cells in this pathology, they do not exclude a contribution by other deficiencies expressed in Wf/Wf mice. In order to obtain conclusive evidence for the role of mast cells, we engrafted cultured bone marrow-derived mast cells (BMMC) from normal mice into their Wf/Wf littermates. After 12 weeks, the hind limbs of Wf/Wf, engrafted Wf/Wf and normal littermates were subjected to IR injury. Muscle viability was assessed by both morphology and by nitroblue tetrazolium histochemical assay. Here, we present conclusive evidence for a causal role of mast cells in IR injury. Our data show that muscles from Wf/Wf mice subjected to IR have a significantly greater proportion of viable fibres than normal littermates subjected to identical injury (78.9+/-5.2 vs 27.2+/-3.7%, respectively). When Wf/Wf IR-resistant mice were engrafted with BMMC from normal littermates and subjected to IR, the proportion of viable muscle fibres was significantly reduced (78.9+/-5.2 vs 37.0+/-6.5%). Thus, engraftment of BMMC into Wf/Wf mice restores the susceptibility of skeletal muscle to IR injury irrespective of other abnormalities in Wf/Wf mice. In this model, the numerical density of mast cells undergoes a significant decrease within 1 h of reperfusion, indicating extensive mast cell degranulation. We conclude that mast cells are pivotal effector cells in the pathogenesis of IR injury of murine skeletal muscle.