The inflammatory response is thought to play important roles in tissue healing. The hypothesis of this study was that the inflammatory cytokine, interferon (IFN)- is produced endogenously following skeletal muscle injury and promotes efficient healing. We show that IFN- is expressed at both mRNA and protein levels in skeletal muscle following injury, and that the time course of IFN- expression correlated with the accumulation of macrophages, T-cells, and NK cells, as well as myoblasts, in damaged muscle. Cells of each type were isolated from injured muscle, and IFN- expression was detected in each cell type. We also demonstrate that administration of an IFN- receptor blocking antibody to wild-type mice impaired induction of interferon response factor-1, reduced cell proliferation, and decreased formation of regenerating fibers. IFN- null mice showed similarly impaired muscle healing associated with impaired macrophage function and development of fibrosis. In vitro studies demonstrated that IFN- and its receptor are expressed in the C2C12 muscle cell line, and that the IFN- receptor blocking antibody reduced proliferation and fusion of these muscle cells. In summary, our results indicate that IFN- promotes muscle healing, in part by stimulating formation of new muscle fibers.