Many single gene disorders are associated with a range of symptoms that cannot be explained by the primary genetic mutation. In humans, this is clearly seen in individuals with the identical loss of function mutation in Sgcg, the gene encoding the dystrophin associated protein gamma-sarcoglycan. Like their human counterparts, Sgcg mice develop progressive muscle wasting and weakness along with dilated cardiomyopathy. To identify genetic regions that modify outcome in muscular dystrophy and cardiomyopathy, we used an intercross strategy. Sgcg mice in the DBA2/J or 129T2/SvEmsJ were intercrossed, representing severe and mild forms of disease, respectively. Nearly 200 mice were analyzed using echocardiography in vivo, and ex vivo analysis of muscle and heart for mass, hydroxyproline content and Evans blue dye uptake as indicators of muscle fibrosis and damage. Genomewide profiling was conducted and identified 40 suggestive QTLs and 12 significant QTLs. A second intercross using the Sgcg allele in the DBA2/J background was generated with the superhealing MRL background. Genomewide analysis identified a locus on chromosome 2 that regulates cardiopulmonary function. These data indicate that mouse models of muscular dystrophy and cardiomyopathy can be used to identify modifier loci that correlate with outcome. The identification of the genes responsible for these QTLs will help define the pathological defects of cardiopulmonary dysfunction.