Duchenne muscular dystrophy (DMD) is a devastating childhood disorder which is characterized by progressive muscle loss and the accumulation of connective tissue. Dampening the inflammatory response is a recognised way of reducing the devastating loss of skeletal muscle in DMD. We have recently shown that expression of ADAMTS5 is dynamically regulated during skeletal muscle regeneration. This suggested a potential role for ADAMTS5-mediated extracellular matrix remodelling in the muscular dystrophy phenotype. We tested this hypothesis by crossing mdx and Adamts5 knockout mice and saw a striking improvement in muscle pathology in mdx:Adamts5-/- mice. There were fewer necrotic fibres identified by IgG staining, and serum creatine kinase, used as marker of muscle damage, was lower, indicating reduced pathological permeability of the muscle cell membrane. In addition, mdx:Adamts5-/- mice had fewer fibres with central nuclei, a marker of past muscle damage, degeneration and regeneration. Macrophage infiltration is reduced in mdx:Adamts5-/- muscle at 12 weeks of age (~50% reduction). This suggests that inflammation is a major pathway modulated in mdx:Adamts5-/- muscle and critically, is the first indication that ADAMTS5 activity may be proinflammatory. This strongly supports the hypothesis that inflammation and fibrosis is mediated or enhanced by a cleaved ADAMTS5 substrate. This indicates that our studies are likely to have implications well beyond DMD. Inhibiting ADAMTS5 may improve outcomes in many other muscular dystrophies where inflammation is increased and, even more broadly, in other conditions involving unregulated inflammation including wound healing, liver cirrhosis and cardiovascular fibrosis. These data demonstrate that ADAMTS5 activity is detrimental in mdx muscle, and open up a new therapeutic approach for muscular dystrophy – inhibiting ADAMTS5.