Plasma vasopressin (AVP) increases after endotoxin administration in freely behaving unanesthetized rats. The present experiments sought to determine the factors that mediate this vasopressin response. Endotoxin (150 micrograms/kg iv) elicited a significant increase in plasma AVP concentration. This response was accompanied by unchanged plasma osmolality, hypotension, increased hematocrit (reflecting decreased plasma volume), hypothermia, and hyperglycemia. Pretreatment with the prostaglandin synthesis inhibitor, indomethacin (5 mg/kg sc), had no effect on the vasopressin response to endotoxin but abolished or significantly attenuated the changes in blood pressure, hematocrit, temperature, and plasma glucose while leaving plasma osmolality unaltered. These investigations indicate that endotoxin stimulates vasopressin secretion into plasma independently of changes in plasma osmolality, systemic blood pressure, plasma volume, body temperature, or plasma glucose. The results also suggest that vasopressin responses to endotoxin are not mediated by prostaglandins, whereas prostaglandins do play a role in endotoxin's effects on blood pressure, plasma volume, temperature, and plasma glucose.