Interleukin-1beta acts on the CNS to induce fever, neuroendocrine activation, and behavioral changes, but cannot passively cross the blood-brain barrier. According to a widely accepted hypothesis interleukin-1beta induces the synthesis of cyclooxygenase-2 at the blood-brain interface, which produces prostaglandins that diffuse into brain parenchyma to activate neurons. We studied the role of brain cyclooxygenase-2 in interleukin-1beta-induced fever, neuroendocrine and behavioral responses and cellular activation by intracerebroventricular infusion of the cyclooxygenase-2 inhibitor NS-398. Central cyclooxygenase-2 inhibition attenuated extracellular signal-regulated kinase-1/2 phosphorylation and c-Fos induction in the median preoptic area and arcuate hypothalamus, but not in other hypothalamic or brainstem structures, after intraperitoneal interleukin-1beta administration. However, the same treatment did not affect interleukin-1beta-induced fever, rises in corticosterone or anorexia. These findings moderate the prevailing view and indicate that brain cyclooxygenase-2-dependent prostaglandin production is important to activation of the median preoptic and arcuate hypothalamus, but not necessarily involved in fever, rises in plasma corticosterone and anorexia after peripheral interleukin-1beta administration.