alpha-Dystroglycan (alpha-DG) is a component of the dystroglycan complex, which is involved in early development and morphogenesis and in the pathogenesis of muscular dystrophies. Here, alpha-DG was shown to serve as a Schwann cell receptor for Mycobacterium leprae, the causative organism of leprosy. Mycobacterium leprae specifically bound to alpha-DG only in the presence of the G domain of the alpha 2 chain of laminin-2. Native alpha-DG competitively inhibited the lminin-2-mediated M. leprae binding to primary Schwann cells. Thus, M. leprae may use Linkage between the extracellular matrix and cytoskeleton through lminin-2 and alpha-DG for its interaction with Schwann cells.