BACKGROUND Coxsackieviruses B (CBVs) are dominant causative agents in myocarditis and are associated with pathogenesis is some cases of dilated cardiomyopathy, a clinical entity with a poor survival without heart transplantation. RESULTS In vitro, the antiviral agent WIN 54 954 was shown to inhibit replication of CBV3 at a minimal inhibitory concentration value of 0.02 mg/L. Administration of WIN 54 954, 100 mg/kg BID PO, beginning on the day of infection resulted in complete protection from enteroviral mortality (P < .01). WIN 54 954 treatment did not abrogate the inflammatory reaction in the myocardium. No difference was found in the expression of surface lymphocyte subset markers. At 3 weeks, macrophages seemed to dominate the inflammatory reaction, regardless of treatment. There was no difference in CBV3 antibody titers, indicating that WIN 54 954 does not interfere with the development of protective immunity. Complement factors C3 and B were synthesized at a higher level during infection and correlated well with the degree of inflammatory reaction. CONCLUSIONS The results show that WIN 54 954 is a potent antiviral agent with a highly significant effect on survival in CBV-induced myocarditis in the A/J mouse if treatment is started early. It is suggested that the reduction in mortality seen with WIN 54 954 administration is due to an inhibitory effect on virus replication in affected organs that does not interfere with cellular or humoral immunity.