The process of inflammation and immune response is regulated by proinflammatory cytokines. Interleukin-6 (IL-6), one of the proinflammatory cytokines, plays a potentially critical role in viral-induced myocarditis. Our previous work demonstrates that exogenous IL-6 administration, given at the time of encephalomyocarditis virus (EMCV) inoculation in C3H/HeJ mice, has a protective effect on myocardium and improves survival rates. In the present study, we examined whether overexpression of IL-6 modified viral myocarditis. On day 3 and 10 after inoculation with EMCV, the ratio of heart weight to body weight and myocardial injury were significantly increased in IL-6 transgenic mice (IL-6TG). On day 3, a reduction of viral clearance was shown by the presence of elevated viral titers and viral replication in the heart of IL-6TG. The concentrations of serum tumor necrosis factor- α (TNF α) were dramatically increased in wild-type mice on day 1, in contrast, this change was not observed in IL-6TG. Treatment with recombinant human TNF (2 μ g) significantly improved viral clearance in the IL-6TG hearts. Thus, overexpression of IL-6 promotes myocardial injury by interrupting both the cytokine network and viral clearance. These experiments suggest the possibility that IL-6 is one of the factors that accelerates tissue damage, including myocardial injury, in the viral myocarditis.