Abstract Description Myocarditis can be triggered by viral infections and mRNA COVID-19 vaccines. While vaccine-associated myocarditis(VAM) shows better outcomes than conventional myocarditis(COM), its mechanisms remain poorly understood. We conducted single-cell RNA sequencing on peripheral blood mononuclear cells from VAM(n = 6) and COM(n = 6) patients, with vaccinated controls(n = 6), during acute and recovery phases. Both conditions showed distinct myeloid cell alterations. We identified novel CCR2-expressing classical monocyte subpopulations specific to myocarditis patients, absent in healthy vaccinated controls. These populations arose from emergency myelopoiesis in response to cardiac injury. VAM exhibited characteristics of inflammasomopathy, while COM showed stronger features of interferonopathy. Type I IFN expression correlated with both CD64 and CCR2 expression, while CCR2hiCD64hi CM associated with cardiac inflammation markers. VAM-specific Th17 cells showed distinct features with elevated expression of CCR6, TNFRSF4, TNFRSF17, FURIN, BHLHE40, and GPR65, sharing transcriptomic features with pathogenic Th17 cells. These cells acquired their unique profile under IL-1 signaling influence. Cardiac tissue analysis from a severe case confirmed both CCR2-expressing monocytes and these Th17 cells within the myocardium. Our study reveals the interplay between inflammasomopathy and interferonopathy in myocarditis immunopathology, providing novel biomarkers for targeted therapeutic strategies. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)