Background: The inflammatory cytokines, such as interleukin-1 (IL-1) and TNF-alpha, can modulate the outcome of virus infection and may enhance its immune sequela. Although there is some evidence that antagonist of TNF-alpha may improve ventricular function and clinical status in congestive heart failure, the effect of TNF-alpha receptor on the viral myocarditis has not been studied well. In this study we transferred soluble p75 TNF receptor linked to the Fc portion of human Immunoglobulin G1 (sTNFR:Fc) gene by in vivo electroporation, and evaluated the effects of expressed sTNFR:Fc on coxsackieviral myocarditis. Methods: A plasmid DNA encoding sTNFR:Fc (15關g/50關l per mouse) was injected into the gastrocnemius muscles of Balb/C male mice (n = 25, sTNFR:Fc mice) followed by electroporation. Control mice were injected with empty vector. After electroporation, the mice were infected with coxsackievirus B3 (100 PFU). Results: 1) The serum levels of sTNFR:Fc increased from day 1 (811pg/ml), peaked at day 5 (2274 pg/ml) and decreased from day 7 (460 pg/ml) and were not detected after day 14 (control serum: 0 pg/ml). 2) The mortality rate of sTNFR:Fc DNA-treated mice was higher than that of control mice for the first 6 days after CVB3 infection (23% versus 5%, sTNFR:Fc versus control, at day 6). After then, control mice were died continuously and the survival rate at day 27 was 0%. In sTNFR:Fc group, the survival rate at day 27 was 36% (p<0.01). 3) In histology, the degrees of inflammation, necrosis and fibrosis of the hearts were significantly decreased in the sTNFR:Fc DNA-treated group at day 12 (p<0.05), while there were no significant differences on day 3 and 7 between sTNFR:Fc DNA-treated group and controls. Conclusion: These results show that in vivo electroporation may be a useful and feasible method to deliver cytokine genes in cardiovascular disease. The elevated sTNFR:Fc modified innate immunity of TNF-alpha during acute phase and suppress inappropriate immune response during subacute phase of viral myocarditis, suggesting that endogenous TNF-alpha may play a differential role according to the stage of the disease.