Myocardial depression in septic shock is well known, but its pathophysiological genesis is incompletely understood. To assess the incidence and extent of stress-induced histologic myocardial alterations in septic shock, a prospective, observational, combined clinical and postmortem study was conducted, and 20 patients dying from septic shock were included. Exclusion criteria were younger than 18 years, pregnancy, open heart surgery or cardiopulmonary resuscitation, acute neurologic diseases, pheochromocytoma, and forensic autopsy. A systematic macropathologic evaluation was performed. Nine predefined heart sections were histologically screened for myocytolysis, interstitial fibrosis, contraction band necrosis, mononuclear infiltrates, interstitial edema, and tissue hemorrhage. Stress-induced pathologies were found in 90% to 100% of patients in all heart sections (myocytolysis, 100%; interstitial fibrosis, 100%; contraction band necrosis, 95%; mononuclear infiltrates, 90%; interstitial edema, 90%; tissue hemorrhage, 30%). The incidence and extent of contraction band necrosis, mononuclear infiltrates, and myocytolysis did not differ between sexes; patients with or without chronic β-blocker, calcium antagonist, and/or statin premedication; or between the binary use of different catecholamine agents (all comparisons P > 0.05). The maximum epinephrine dose correlated with the overall extent of mononuclear infiltrates (Spearman-Rho, r = 0.704; P = 0.05) and myocytolysis (Spearman-Rho, r = 0.933; P = 0.001). Maximum norepinephrine doses correlated with the extent of mononuclear infiltrates in the left ventricular anterior wall (Spearman-Rho, r = 0.519; P = 0.02). The total duration of catecholamine therapy was correlated with the extent of mononuclear infiltrates in the apex (Spearman-Rho, r = 0.571; P = 0.009) and right atrium (Spearman-Rho, r = 0.535; P = 0.02). In conclusion, our results suggest that histologic lesions potentially indicative of stress-induced cardiotoxicity can be observed in most patients dying from septic shock.