The histopathologic features reflecting the influence of virus genotype and host differences on myocarditis were evaluated in six inbred mouse strains (C57BL/6, B10.D2, BALB/c, DBA/2, A/J, and C3H/HeJ) inoculated with four respective variants of coxsackievirus B3 (CVB3-CG, -SH, -ST, or -NR). The most severe and most prevalent histologic lesions occurred after infection with CVB3-SH or -CG variants, regardless of mouse strain. In general, C57BL/6 mice showed the lowest susceptibility to myocarditis while A/J or C3H/HeJ animals had the highest susceptibility, whether early (7 days) or late (21 days) after CVB3 inoculation. Lesion size and calcification depended to an extent on disease severity, but calcification in the C3H/HeJ myocardium was notably sparse. Lesions clustered distinctly in the midthird of the ventricular wall in some animals, particularly in DBA/2 mice. Extensive pericarditis occurred exclusively in BALB/c and DBA/2 animals and predominated over the right ventricle anterolaterally. Virus titer in the heart did not account for disease susceptibility among mouse strains. These characteristics reflect differences in pathogenicity and are important considerations in the study of mechanisms in CVB3-induced myocarditis in mice.