Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disease caused by mutations in the gene encoding dystrophin. Loss of dystrophin results in reduced sarcolemmal integrity and increased susceptibility to muscle damage. The α
7
β
1
-integrin is a laminin-binding protein up-regulated in the skeletal muscle of DMD patients and in the
mdx
mouse model. Transgenic overexpression of the α
7
-integrin alleviates muscle disease in dystrophic mice, making this gene a target for pharmacological intervention. Studies suggest laminin may regulate α
7
-integrin expression. To test this hypothesis, mouse and human myoblasts were treated with laminin and assayed for α
7
-integrin expression. We show that laminin-111 (α
1
, β
1
, γ
1
), which is expressed during embryonic development but absent in normal or dystrophic skeletal muscle, increased α
7
-integrin expression in mouse and DMD patient myoblasts. Injection of laminin-111 protein into the
mdx
mouse model of DMD increased expression of α
7
-integrin, stabilized the sarcolemma, restored serum creatine kinase to wild-type levels, and protected muscle from exercised-induced damage. These findings demonstrate that laminin-111 is a highly potent therapeutic agent for the
mdx
mouse model of DMD and represents a paradigm for the systemic delivery of extracellular matrix proteins as therapies for genetic diseases.