The sarcoglycanopathies are a group of four autosomal recessive limb girdle muscular dystrophies (LGMD 2D, 2E, 2C, and 2F), caused by mutations of the α-, β-, γ-, or δ-sarcoglycan genes, respectively. The δ-sarcoglycan-deficient hamster has been the most utilized model for gene delivery to muscle by recombinant adeno-associated virus (AAV) vectors; however, human patients with δ-sarcoglycan deficiency are exceedingly rare, with only two patients described in the United States. Here, we report construction and use of AAV vectors expressing either α- or β-sarcoglycan, the genes responsible for the most common forms of the human sarcoglycanopathies. Both vectors showed successful short-term genetic, biochemical, and histological rescue of both α- and β-sarcoglycan-deficient mouse muscle. However, comparison of persistence of expression in 51 injected mice showed substantial differences between AAV α-sarcoglycan (α-SG) and β-sarcoglycan (β-SG) vectors. AAV-β-SG showed long-term expression with no decrease in expression for more than 21 months after injection, whereas AAV-α-SG showed a dramatic loss of positive fibers between 28 and 41 days post-injection (p = 0.006). Loss of immunopositive myofibers was correlated with significant inflammatory cell infiltrate, primarily macrophages. To determine whether the loss of α-sarcoglycan-positive fibers was due to an immune response or cytotoxic effect of α-sarcoglycan overexpression, severe combined immunodeficient (SCID) mouse muscle was assayed for cytotoxicity after injection with AAV-α-SG, AAV-β-SG, or phosphate-buffered saline. The results were consistent with overexpression of α-sarcoglycan causing significant cytotoxicity. The cytotoxicity of α-sarcoglycan, and not β- or δ-sarcoglycan overexpression, was consistent with biochemical studies of the hierarchical order of assembly of the sarcoglycan complex. Our data suggest that even closely related proteins might require different levels of expression to avoid toxicity and achieve long-term tissue rescue.