Idiopathic dilated cardiomyopathy (DCM) is a disease of putative autoimmune origin that kills males at a twofold to threefold greater frequency than females. The reasons underlying these differential outcomes may be related to sex-divergent self-recognition. Here we examined sex-specific autoimmune responses to cardiac self and their impact on DCM development. We found that males immunized to the p406-425 peptide derived from mouse cardiac alpha-myosin heavy chain preferentially develop a predominant Th17 lineage response that provides sustained T-cell memory and a high DCM incidence whereas females preferentially develop a predominant Th1 lineage response that becomes anergized to cardiac self resulting in compensatory protection against DCM. The distinct sex-defined disease phenotypes are interchangeable after in vivo manipulation of Th1 (interleukin-2) and Th17 (interleukin-17) cytokines. Our study shows that male and female SWXJ mice differentially respond to cardiac self in ways that lead to distinct autoimmune outcomes and implies that optimized therapy for autoimmunity may require consideration of the qualitatively different ways that males and females engage self.