Introduction: The injury caused by reperfusion of ischemic skeletal muscle is mediated by the membrane attack complex of complement (C) (Am J Phys 1999; 277:1263). This C activation results from local classical pathway activation after deposition of IgM in injured muscle, in analogy to gut reperfusion injury (J Appl Phys 1999; 86:938). This study was performed to elucidate the exact site of C and IgM deposition in tissue injured by ischemia and reperfusion. Methods: C57Bl/6 mice were subjected to 2 hours of tourniquet-induced hindlimb ischemia followed by reperfusion for 0–6 hours. Three muscle groups (vastus, gastrocnemius, soleus) of varying fast-myosin content were compared for muscle fiber damage and C deposition. Adjacent paraffin embedded cross-sections were immunostained to correlate C3 deposition with muscle fiber type as defined by monoclonal antibodies. Results: Muscle injury after ischemia and reperfusion is not uniform and not all fibers in the same microscopic field are affected. Damaged fibers are also those to which C3 and IgM bind, exclusively. Immunostaining for slow twitch (Type I) or fast twitch (Type II) fibers reveals that injury and C3 deposition is confined to Type II fibers with lower myosin content. A correlation of Type II fiber content and degree of muscle injury showed that the predominantly fast-twitch vastus muscle had greatest number of damaged fibers per 10x field (28.2 ± 12.4) when compared to the mixed fiber-type gastronemius muscle (20.5 ± 5.3) and the mixed, but slow-twitch enriched soleus muscle (17.3 ± 11.8). Conclusion: Complement activation and skeletal muscle reperfusion injury occurs predominantly on Type II fibers with low myosin content. This suggests that attempts to control the post-reperfusion inflammation will likely produce substantial muscle recovery. Furthermore, the basis of the complement activation may be revealed in the comparison of the two muscle fiber types.