Familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder caused by mutationally altered dominant-acting sarcomere proteins, exhibits significant clinical heterogeneity. To determine whether genetic background could influence the expression of this disease, we studied a murine model for this human condition. Hypertrophic responses to the Arg403Gln missense mutation in a cardiac myosin heavy chain gene were compared in 129SvEv (inbred; designated 129SvEv-α MHC^403/+) and Black Swiss (outbred; designated BSw- α MHC^403/+) strains. At 30–50 weeks of age all 129SvEv- α MHC^403/+showed left ventricular hypertrophy, while left ventricular wall thickness was increased in only half of BSw- α MHC^403/+mice demonstrating that a polymorphic modifier gene can determine the hypertrophic response to this dominant-acting sarcomere protein mutation. Further analysis suggests that SJL/J mice bear a recessive allele of this modifier gene that prevents a hypertrophic response to the Arg403Gln missense mutation. We conclude that genetic modifiers in mice, and presumably in man, can alter the hypertrophic response to sarcomere protein gene missense mutations.