Neuropathic complication often occurs in critically ill patients, and changes in the microcirculation of the peripheral nerve have been suggested to play a role in the pathogenesis of the nerve lesion. We report the results of a pathological and immunohistochemical study of superficial peroneal nerve biopsy specimens in a series of 22 critically ill patients with sepsis and neuromuscular disorders. Eight patients had histopathological features of axonal neuropathy compatible with critical illness polyneuropathy (CIP). The nerve lesions ranged in severity from mildly reduced myelin-fiber density with sporadic axonal degeneration to marked fiber loss with abundant degenerative changes. In no patient did we detect evidence of primary demyelinization or inflammatory infiltrates. We analyzed the immunohistochemical expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF-alpha) in nerve microvessels. Expression of E-selectin was significantly increased in endothelium of epineurial and endoneurial vessels, suggesting endothelial cell activation. These findings again confirm axonal degeneration as the major pathological feature of CIP. Our immunohistochemical data provide first evidence that activation of the endothelial cells of the microvessels in the endoneurium of human peripheral nerve does occur during sepsis. This specific activation might have implications with the mechanisms responsible for the axonopathy in critically ill patients.