To examine the role of myocardial interleukin-6 (IL-6) in myocardial inflammation and dysfunction after burn complicated by sepsis, we performed 40% total body surface area contact burn followed by late (7 days) S. pneumoniae pneumonia sepsis in wild type (WT) mice, IL-6 knockout (IL-6 KO) mice, and transgenic mice over-expressing IL-6 in the myocardium (TG). Heart and total body weight were recorded. Twenty-four hours after sepsis was induced, isolated cardiomyocytes were harvested and cultured in vitro, and supernatant concentrations of IL-6 and tumor necrosis factor (TNF)- were measured. Cardiomyocyte intracellular calcium calcium ([Ca²⁺]_i) and sodium ([Na⁺]_i) concentrations were also determined. Separate mice in each group underwent in vivo global hemodynamic and cardiac function assessment by cannulation of the carotid artery and insertion of a left ventricular pressure volume conductance catheter. Hearts from these mice were collected for histopathologic assessment of inflammatory response, fibrosis, and apoptosis. In the WT group, there was an increase in cardiomyocyte TNF- , [Ca²⁺]_i and [Na⁺]_i after burn plus sepsis, along with cardiac contractile dysfunction, inflammation and apoptosis. These changes were attenuated in the IL-6 KO group but accentuated in the TG group. We conclude myocardial IL-6 mediates cardiac inflammation and contractile dysfunction after burn plus sepsis.