Impaired arginine vasopressin (AVP) synthesis and release by the neurohypophyseal system, which includes the neurohypophysis and magnocellular neurons of the paraventricular and supraoptic nuclei, have been postulated in septic shock, but changes in this system have never been assessed in human septic shock, and only partially experimentally. We investigated AVP synthesis and release by the neurohypophyseal system in 9 patients who died from septic shock and 10 controls, and in 20 rats with fecal peritonitis-induced sepsis and 8 sham-operation controls. Ten rats died spontaneously from septic shock, and the others were sacrificed. In patients with septic shock, as in rats that died spontaneously following sepsis induction, AVP immunohistochemical expression was decreased in the neurohypophysis and supraoptic magnocellular neurons, whereas it was increased in the paraventricular magnocellular neurons. No significant change was observed in AVP messenger RiboNucleic Acid (mRNA) expression assessed by in situ hybridization in either paraventricular or supraoptic magnocellular cells. This study shows that both in human and experimental septic shock, AVP posttranscriptional synthesis and transport are differently modified in the magnocellular neurons of the supraoptic and paraventricular nuclei. This may account for the inappropriate AVP release in septic shock and suggests that distinct pathogenic mechanisms operate in these nuclei.