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Septic cardiomyopathy is a severe complication of sepsis and septic shock. This study aimed to evaluate the role of thrombomodulin and its lectin-like domain (LLD-TM) in the development of septic cardiomyopathy and the link between LLD-TM, HMGB-1, and toll-like receptors 2/4 (TLR 2/4) to intracellular mechanisms resulting in reduced cardiac function.Sepsis was induced using a polymicrobial peritoneal infection model in wildtype and mice lacking the lectin-like domain of thrombomodulin (TMLack of the LLD-TM results in a significant increase in severity of disease, decreased survival and impaired cardiac function in septic mice. In vivo and in vitro analyses of cardiomyocytes displayed high levels of inflammatory cytokines causing cardio-depression. In vitro results showed a strong correlation between elevated HMGB-1 levels and elevated troponin-1 levels. No connection was found between HMGB-1 and TLR-2 and/or -4 signalling pathways. Phospholamban mediated dysregulation of calcium homeostasis resulted in a general impairment after sepsis induction, but showed no connection to LLD-TM.Lack of LLD-TM results in an increase in general severity of disease, decreased survival and impaired cardiac function in sepsis. TLR-2 and TLR 4 do not participate as mediating factors in the development of septic cardiomyopathy.