Objective: To test the hypothesis that activation of peroxisome proliferator activated receptor c (PPAR-c) reduces experimental autoimmune myocarditis (EAM) associated with inhibitor kB (IkB) a induction, blockade of nuclear factor kB (NF-kB), and inhibition of inflammatory cytokine expression. Methods: EAM was induced in Lewis rats by immunisation with porcine cardiac myosin. PPAR-c activators 15-deoxy-D12, 14-prostaglandin J2 (15d-PGJ2) and pioglitazone (PIO) were administrated to rats with EAM. Results: Enhanced PPAR-c expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of 15d-PGJ2 and PIO greatly reduced the severity of myocarditis and suppressed myocardial mRNA and protein expression of inflammatory cytokines in rats with EAM. In addition, treatment with PPAR-c activators enhanced IkB concentrations in the cytoplasmic fractions and nuclear fractions from inflammatory myocardium. Concurrently, NF-kB was greatly activated in myocarditis; this activation was blocked in the 15d-PGJ2 treated and PIO treated groups. Conclusions: PPAR-cmay have a role in the pathophysiology of EAM. Because an increase in IkB expression and inhibition of translocation of the NF-kB subunit p65 to the nucleus in inflammatory cells correlated with the protective effects of PPAR-c activators, these results suggest that PPAR-c activators act sequentially through PPAR-c activation, IkB induction, blockade of NF-kB activation, and inhibition of inflammatory cytokine expression. These results suggest that PPAR-c activators such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.