To facilitate gene and cell therapy experiments, we created severely immune-deficient mouse models of Duchenne muscular dystrophy (DMD), limb girdle muscular dystrophy 2B (LGMD2B), and limb girdle muscular dystrophy 2D (LGMD2D) by crossing mdx4Cv, Bl/AJ, and Sgca-null mice with NRG immune-deficient mice. The resulting mdx4Cv/NRG, BlAJ/NRG, and Sgca/NRG mice demonstrated the presence of the appropriate mutant alleles at Dmd, Dysf, Sgca, Rag1, and Il2rγ by genotyping PCR. Absence of dystrophin, dysferlin, or α-sarcoglycan protein was confirmed by western blot and immunohistochemistry. We performed centronucleation, Evans blue dye, hydroxyproline, and treadmill assays on the disease model mice versus NRG controls to evaluate muscle histology and function. These studies demonstrated that the mdx4Cv/NRG and Sgca/NRG mice showed significant deficits in muscle structure and function in all the assays and were similar to each other. By contrast, the phenotype of the BlAJ/NRG mice was milder in each case. The results we observed parallel the phenotypes seen in patients with the corresponding disorders. These novel immune-deficient mouse models of DMD, LGMD2B, and LGMD2D will be useful for long-term gene and cell therapy studies involving transfer of foreign genes and cells.