Lymphocytic myocarditis is a common condition associated with both infectious diseases and immunological disorders, and is often associated with severe morbidity and mortality, but few effective treatments. In many cases, the pathophysiology involves a failure of central and/or peripheral immune tolerance leading to a cardiac-specific autoimmune T cell response. Previous studies indicate that the PD-1:PD-L1 axis plays an important role in limiting inflammation in the heart. CpG ODN are TLR9 agonists with known immunoregulatory capacity, in part through their potent induction of type I IFN, a known inducer of PD-L1. In this study, we used human tissue to determine the signature of PD-L1 expression in myocarditis. Furthermore, we investigated the in vitro activity of CpG ODN as an inducer of PD-L1 in the heart, and tested if this activity is dependent on type I IFN. Lastly, we sought to establish the cardioprotective potential of CpG ODN in a CD8+ T cell-mediated adoptive transfer model of myocarditis in mice. Myocarditic human hearts demonstrate elevated PD-L1 relative to healthy hearts, indicating a possible feedback inhibition on inflammation of translational relevance. CpG ODN robustly upregulates PD-L1 and interferon-related genes in the myocardium, though our data is equivocal as to whether this is a type I IFN-dependent process. Pretreatment of mice with CpG ODN significantly reduced the extent of CD8+ T cell-medaited disease as measured by both histology and serology. Though results did not reach statistical significance, preliminary data suggests that this cardioprotection may not be fully dependent upon PD-1:PD-L1 activity. CpG ODN is known to have other immunoregulatory properties, and our data on gene expression in hearts of treated mice suggest other regulatory mechanisms by which CpG ODN may regulate autoimmunity in the heart. Irrespective of the mechanism of action, this study provides evidence of the possible therapeutic utility of CpG ODN as a targeted therapy for myocarditis.