Potassium-induced cortical spreading depression (CSD) on prostaglandin E1 (PGE1) induced fever has been investigated in a dose-responsive experimental design in both conscious and urethane-anesthetized adult male Sprague-Dawley rats. While CSD in itself had no effect on nonfebrile body temperature even under cold ambient conditions, CSD significantly suppressed small but not large fevers induced by intracerebroventricular PGE1. The increased oxygen consumption during fever was also reduced. We also explored the possible involvement of the antipyretic peptide arginine vasopressin, in the CSD-induced suppression of fever. Long term castrated rats have significantly reduced ventral septal levels of this peptide, yet CSD was effective in suppressing the initial 40 min of PGE1 fever in these animals. Thus we conclude that increased release of ventral septal arginine vasopressin is probably not involved in the action of CSD on fever.