Tumor necrosis factor (TNF) and interferon gamma (IFN-γ) are pleuripotent cytokines and have multiple functions during the inflammatory response. Using a murine model of autoimmune myocarditis, we studied the role of TNF and IFN-γ in myocardial inflammation. Neutralizing monoclonal antibodies against TNF-α/β and IFN-γ were administered to myosin-immunized A/J mice to assess the effect on the severity of myocardial inflammation. Anti-TNF treatment significantly reduced the severity of myocarditis compared with rat immunoglobulin G or saline controls (p < 0.0007) when given before myosin immunization. Myosin-specific lymph node T-cell proliferation studies showed no difference in the proliferative response between the anti-TNF-treated mice and controls. Administration of anti-TNF to mice after myosin immunization had no effect on the severity of inflammation. This suggests that TNF is an important mediator early in the pathogenesis of myocardial inflammation in this model of myocarditis. Neutralization of IFN-γ significantly increased the severity of myocarditis compared with rat immunoglobulin G and saline controls (p < 0.0065), suggesting that IFN-γ may function as an important regulatory cytokine early in the pathogenesis of myocardial inflammation. Understanding the functions of cytokines during the inflammatory response to myocardial injury may provide important information on possible methods to limit myocardial damage.