The present study investigated the febrile response in zymosan-induced arthritis, as well as the increase in PGE₂concentration in the cerebrospinal fluid (CSF), along with the effects of antipyretic drugs on these responses in rats. Zymosan intra-articularly injected at the dose of 0.5 mg did not affect the body core temperature (Tc) compared with saline (control), whereas at doses of 1 and 2 mg, zymosan promoted a flattened increase in Tc and declined thereafter. The dose of 4 mg of zymosan was selected for further experiments because it elicited a marked and long-lasting Tc elevation starting at 3 1/2 h, peaking at 5 1/2 h, and remaining until 10 h. This temperature increase was preceded by a decrease in the tail skin temperature, as well as hyperalgesia and edema in the knee joint. No febrile response was observed in the following days. In addition, zymosan-induced fever was not modified by the sciatic nerve excision. Zymosan increased PGE₂concentration in the CSF but not in the plasma. Oral pretreatment with ibuprofen (5–20 mg/kg), celecoxib (1–10 mg/kg), dipyrone (60–240 mg/kg), and paracetamol (100–200 mg/kg) or subcutaneous injection of dexamethasone (0.25–1.0 mg/kg) dose-dependently reduced or prevented the fever during the zymosan-induced arthritis. Celecoxib (5 mg/kg), paracetamol (150 mg/kg), and dipyrone (120 mg/kg) decreased CSF PGE₂concentration and fever during zymosan-induced arthritis, suggesting the involvement of PGE₂in this response.