During the early phase of endotoxic shock the hypothalamus is activated and neurohypophyseal hormone secretion is increased. In order to study the participation of the subfornical organ (SFO) in this response we lesioned the nucleus and determined hormone secretion and c-fos expression in the paraventricular and supraoptic nuclei after administration of lipopolysaccharides (LPS) in rats. LPS significantly increased the number of cells showing Fos immunoreactivity in the paraventricular and supraoptic nuclei of the hypothalamus (p < 0.05) and also caused an increase in plasma levels of vasopressin and oxytocin (p < 0.05). SFO lesion significantly reduced LPS-induced Fos immunoreactivity (p < 0.05) and hormone secretion (p < 0.05). We conclude that the SFO participates in the activation of the hypothalamic-neurohypophyseal axis in the early phase of endotoxic shock.