Introduction: Hypertrophic cardiomyopathy (HCM) is a disease caused primarily by sarcomere gene mutations [like myosin-binding protein C3 ( MYBPC3 )], with several distinct phenotypes. Tissue-level inflammation has been reported in human HCM, tissue-specific neutrophil subsets, and their dysregulation cause inflammatory myopathies, and neutrophil extracellular traps (NETs) are associated with cardiac fibrosis in aged rodents. However, the mechanism(s) responsible for the broad phenotypic variability and changes observed over time transitioning from HCM to dilated cardiomyopathy (DCM) has not yet been elucidated. Objective: To determine the cardiac inflammatory signature of HCM and transition from HCM to DCM and its relationship to fibrosis and ventricular remodeling in an established MYBPC3 ( cMyBP-C t/t ) mouse model. Method and Results: Mixed-gender cMyBP-C +/+ (WT) and mutant mice ( cMyBP-C t/t ) underwent echocardiography and were euthanized at one, two and three months of age (n=8) and blood and hearts were harvested. Echocardiography and histopathology examination confirmed significant heart dysfunction and tissue remodeling in cMyBP-C t/t mice showing cardiac hypertrophy at one month of age (Left ventricular (LV) posterior wall systole 1.20 ±0.39 vs 1.51±0.49 and LV posterior wall diastole 0.96 ±0.22 vs 1.38 ±0.36 mm; * p<0.05 ), and DCM phenotype (LV internal diameter systole 2.40 ±0.41 vs 3.67 ±0.25 and LV internal diameter diastole 3.44 ±0.29 vs 4.30 ±0.39 mm; * p<0.05 ) along with myofibrillar loss and increased cardiac fibrosis at three months. Interestingly, LV dysfunction and hypertrophy resulted in a time-dependent increase in the activation of coagulation, as measured by plasma microvesicle tissue factor activity, thrombin antithrombin, and D-dimer. In silico analysis of RNA-Seq data from 3-months old cMyBP-C t/t mice heart revealed key genes and pathways associated with HCM, DCM, tissue remodeling, renin-angiotensin-aldosterone signaling, fibrosis, apoptosis, NETosis, and inflammation. Conclusions: The transition from HCM to a DCM phenotype involves proinflammatory and profibrotic signaling. Therapies directed at tissue-specific inflammation and NETs may be a novel and impactful strategy for HCM.