OBJECTIVE: The present study describes intercalated disc remodeling under both protein expression and structural features in experimental severe sepsis induced by cecal ligation and puncture in mice. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male C57BL/6 mice. INTERVENTIONS: Mice were submitted to moderate and severe septic injury by cecal ligation and puncture. MEASUREMENT AND MAIN RESULTS: Severe septic injury was accompanied by a large number of bacteria in the peritoneal cavity and blood, high levels of tumor necrosis factor-alpha, and monocyte inflammatory protein-1alpha in the septic focus and serum, marked hypotension, and a high mortality rate. Western blot analysis and immunofluorescence showed a marked decrease of key gap and adherens junction proteins (connexin43 and N-cadherin, respectively) in mice submitted to severe septic injury. These changes may result in the loss of intercalated disc structural integrity, characterized in the electron microscopic study by partial separation or dehiscence of gap junctions and adherens junctions. CONCLUSIONS: Our data provide important insight regarding the alterations in intercalated disc components resulting from severe septic injury. The intercalated disc remodeling under both protein expression and structural features in experimental severe sepsis induced by cecal ligation and puncture may be partly responsible for myocardial depression in sepsis/septic shock. Although further electrophysiological studies in animals and humans are needed to determine the effect of these alterations on myocardial conduction velocity, the abnormal variables may emerge as therapeutic targets, and their modulation might provide beneficial effects on future cardiovascular outcomes and mortality in sepsis.