Dystrophic muscle is characterized by chronic injury and a steady recruitment of inflammatory Ly6C hi monocytes. Recent studies have identified the spleen as the dominant reservoir of these cells during chronic inflammation. Here, we investigated the contribution of splenic Ly6C hi monocytes to dystrophic muscle pathology. Using the mdx mouse model of muscular dystrophy, we show that Ly6C hi monocytes accumulate in great numbers in the spleen over the course of the disease. The chemokine receptor CCR2 was upregulated on Ly6C hi monocytes in mdx spleen before disease onset, thereby enabling their recruitment to dystrophic muscle. Splenectomy performed before disease onset significantly reduced the number of Ly6C hi monocytes infiltrating dystrophic limb muscle. Moreover, in the absence of splenic Ly6C hi monocytes there was a significant reduction in dystrophic muscle inflammation and necrosis, along with improved regeneration during early disease. However, during late disease, a lack of splenic Ly6C hi monocytes adversely affected muscle fiber repair, due to a delay in the phenotypic shift of proinflammatory F4/80+ Ly6C hi CD206 lo to antiinflammatory F4/80+ Ly6C lo CD206+ macrophages. Overall, we show that the spleen is an indispensable source of Ly6C hi monocytes in muscular dystrophy and that splenic monocytes are critical players in both muscle fiber injury and repair.