Male BALB/c, DBA/2 and A mice inoculated with a myocarditic variant of coxsackievirus group B, Type 3 (CVB3) developed three distinct patterns of myocarditis. Most BALB/c and all DBA/2 mice developed acute cardiac inflammation lasting only 2 weeks, while A animals consistently showed twice as much myocardial damage as the other two strains, with active myocarditis continuing for 56 days after virus inoculation. Although virus elimination from the heart was also delayed in A mice, immunopathogenic, not viral, mechanisms caused cardiac injury in all strains. In vivo depletion of L3T4+ (T helper) and Lyt 2+ (T cytolytic/suppressor) cells using monoclonal antibodies showed that myocarditis in BALB/c mice depended predominantly on Lyt 2+ cells, in DBA/2 mice on L3T4+ cells and in A mice on both Lyt 2+ and L3T4+ cells. IgM heart reactive antibodies (HRAs) occurred in all three strains, while IgG HRAs were detected only in DBA/2 and A mice. Presumably, only the IgG antibody was pathogenic in this system. These data suggest that the host's genetic makeup determines the type of immune response to CVB3 infection of the heart and therefore the pattern of myocarditis which develops.