To determine critical role of cyclooxygenase-2 (COX-2) for development of viral myocarditis, a mouse model of encephalomyocarditis virus-induced myocarditis was used. The virus was intraperitoneally given to COX-2 gene-deficient heterozygote mice (COX-2+/-) and wild-type mice (WT). We examined differences in heart weights, cardiac histological scores, numbers of infiltrating or apoptotic cells in myocardium, cardiac expression levels of COX-2, tumor necrosis factor-alpha (TNF-alpha), and adiponectin mRNA, immunoreactivity of COX-2, TNF-alpha, and adiponectin in myocytes, cardiac concentrations of TNF-alpha and adiponectin, prostaglandin E2 (PGE2) levels in hearts, and viral titers in tissues between COX-2+/- and WT. We observed significantly decreased expression of COX-2 mRNA and reactivity in hearts from COX-2+/- on day 8 after viral inoculation as compared with that from WT, together with elevated cardiac weights and severe inflammatory myocardial damage in COX-2+/-. Cardiac expression of TNF-alpha mRNA, reactivity, and protein on day 8 was significantly higher in COX-2+/- than in WT, together with reciprocal expression of adiponectin mRNA, reactivity, and protein in hearts. Significantly reduced cardiac PGE2 levels on day 8 were found in COX-2+/- compared with those in WT. There was no difference in local viral titers between both groups on day 4. Infected WT treated with a selective COX-2 inhibitor, NS-398, also showed the augmented myocardial damage on day 8. These results suggest that inhibition of COX-2 may enhance myocardial damage through reciprocal cardiac expression of TNF-alpha and adiponectin in a mouse model of viral myocarditis.