Abstract Body: Peripartum cardiomyopathy (PPCM) affects approximately 1 in 2,000 live births worldwide and disproportionately impacts women of color, who experience the disease at nearly four times the rate of white women. Despite its substantial morbidity and mortality—including a ~25% fatality rate in the United States—PPCM remains under investigated, with limited understanding of its genetic and mechanistic underpinnings. To model genetically predisposed PPCM, we generated a CRISPR-engineered mouse harboring a truncating variant in Titin (TTN^W26135*/+) based on clinical genetic testing from a UVA pedigree containing dilated cardiomyopathy (DCM) and PPCM. Under basal conditions, TTN^W26135*/+ mice exhibited preserved cardiac structure and function. However, exposure to a single pregnancy and lactation period was sufficient to induce a robust cardiomyopathic phenotype, characterized by increased heart mass, cardiomyocyte hypertrophy, and a reduction in left ventricular ejection fraction to <40%, driven predominantly by systolic dysfunction. These findings establish a humanized TTN^W26135*/+ mouse model that recapitulates key features of PPCM. Systemically, TTN^W26135*/+ mice demonstrated significantly elevated circulating TNFα in plasma and in T cells (CD3+, CD4–, CD8–) isolated from whole blood following pregnancy. This inflammatory signature parallels prior observations from women with PPCM compared with healthy pregnant controls. Transcriptomic profiling of primary cardiomyocytes isolated postpartum revealed significant enrichment of Gene Ontology categories related to “Chemotaxis” and “Regulation of Leukocyte Chemotaxis,” indicating activation of immune-recruitment pathways within cardiomyocytes. Consistent with this, myocardial tissue from postpartum TTN^W26135*/+ mice displayed increased infiltration of CD4+ and CD8+ T cells, along with enhanced IgG deposition relative to wild-type littermates. Notably, cardiomyocyte RNA-seq also identified upregulation of autoimmune-associated gene signatures. Collectively, these findings establish a clinically relevant, humanized TTN^W26135*/+ mouse model of PPCM and identify a previously underappreciated mechanism linking titin truncation to postpartum immune activation and myocardial autoimmunity. This model provides a powerful preclinical platform to interrogate immune-driven mechanisms of PPCM and to evaluate targeted therapeutic strategies aimed at modulating T-cell activation and autoimmune signaling postpartum.