Infection of adult male C3H/HeJ mice with a host range variant of Coxsackievirus B3 (CB3W-RD) induced resistance in these mice to an otherwise lethal dose of Coxsackievirus B1 (CB1). The protective effect induced by CB3W-RD was detectable as early as 1 day post-vaccination and was still present 10 weeks later. While untreated mice infected with CB1 died within 5 days because of massive hepatic necrosis, the liver was spared in mice immunized with CB3W-RD and then challenged with CB1. In general, CB1 titers in heart, liver, and pancreas of CB3W-RD-vaccinated animals were lower than that found in unvaccinated animals. Virus neutralizing antibody was not a mediator of this heterotypic, virus-induced protective effect. In addition, the outcome of CB1 infection could be modified if superinfection with CB3W-RD took place within 1-4 days following CB1 infection. In this regard, maximum therapeutic efficacy was observed when CB1 infected mice were superinfected 2 days after CB1 infection. CB1-infected mice that survived as a result of treatment with CB3W-RD exhibited liver regeneration but did develop myocardial necrosis.