Recombinant adeno-associated virus (rAAV) vectors allow efficient gene transfer and expression in the muscle; therefore, rAAVs represent a potential gene therapy vector for muscular dystrophies. For further investigations, we used a mouse muscular dystrophy model (gsg^-/- mice) γ-sarcoglycan, a subunit of the dystrophin-glycoprotein complex, is missing. gsg^-/- mice develop progressive dystrophy representative of a severe human phenotype disease. We previously showed high levels and stable expression of γ-sarcoglycan in myofibers after direct muscle injection into gsg^-/- mice of a recombinant AAV vector (AAV.dMCK.gSG) carrying the γ-sarcoglycan cDNA driven by a muscle-specific promoter (truncated version of muscle creatine kinase). Here, we show that when γ-sarcoglycan expression is driven by the ubiquitous cytomegalovirus (CMV) promoter (AAV.CMV.gSG), lower levels of transgene expression are observed and are associated with a humoral response to γ-sarcoglycan. When using an rAAV vector, expressing the highly immunogenic product γ-galactosidase under the CMV promoter (AAV.CMV.LacZ), we measured a strong cellular and humoral immune response to the transgene after intramuscular injection into gsg^-/- mice. This study suggests that restriction of transgene expression to the muscle is an important criterion for the treatment of muscular dystrophies and will aid in the design of protocols for gene therapy.