alpha-Dystroglycan, a 156 kDa dystrophin-associated glycoprotein, binds laminin in skeletal muscle. Here we demonstrate that alpha-dystroglycan is a binding protein of laminin (A/B1/B2) and merosin (M/B1/B2) in peripheral nerve. Immunocytochemical analysis demonstrates the localization of alpha-dystroglycan and merosin surrounding myelin sheath of peripheral nerve fibers. Biochemical analysis demonstrates that the 120 kDa peripheral nerve alpha-dystroglycan binds merosin as well as laminin. The binding of laminin and merosin is Ca2+ dependent and is inhibited by NaCl and heparin. Recently, merosin was shown to be deficient in the peripheral nerve of dy mice which have defects in myelination. The interaction between alpha-dystroglycan and merosin may play a role in the regulation of Schwann cell myelination and/or maintenance of myelin sheath.