Previously, we showed that the M1 gene (encoding a viral core protein, mu 2, whose function is unknown) was associated with the efficiently myocarditic phenotype of a reovirus variant, 8B. Here, we have extended our genetic analysis of 8B and conducted genetic analyses of two other reovirus strains (T1L [serotype 1 strain Lang] and Abney). Our results demonstrate that multiple viral core proteins are determinants of reovirus-induced myocarditis. In contrast to our previous association of mu 2 with induction of myocarditis, this provides strong evidence that a core function achieved through the interaction of multiple core proteins is responsible for induction of the disease.