This study compared the antipyretic effects of ibuprofen and indomethacin regarding the efficacy in blocking fevers induced by lipopolysaccharide (LPS from E. coli) or pyrogenic mediators that act on prostaglandin (PG)-dependent and PG-independent pathways. The content of PGE2 in the cerebrospinal fluid (CSF) and the dependence on central arginine vasopressin (AVP) release by both antipyretics were also compared during the reduction of LPS-induced fever. Finally, we investigated the effect of ibuprofen on hypothalamic cytokine content during LPS-induced fever. Ibuprofen (intraperitoneally, i.p.) dose-dependently inhibited the fever induced by LPS (intravenously, i.v.). Indomethacin (2 mg/kg) and ibuprofen (10 mg/kg) reduced the fever induced by i.c.v. injection of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, or arachidonic acid (AA). Ibuprofen, but not indomethacin, inhibited i.c.v. endothelin-1- and pre-formed pyrogenic factor (PFPF)-induced fever. Neither ibuprofen nor indomethacin affected fever by PGE2, PGF2α, or corticotrophin-releasing factor (CRF); however, both reduced the CSF PGE2 content after LPS. Bilateral injection of the AVP V1 receptor antagonist d(CH2)5Tyr(Me)AVP into the ventral septal area blocked both ibuprofen- and indomethacin-induced antipyresis. Ibuprofen did not modify the hypothalamic increase in either IL-1β or IL-6 induced by LPS. In conclusion, although the antipyretic effect of ibuprofen involves the blockage of central production of PGE2 and the endogenous release of AVP, differently from low dose of indomethacin, ibuprofen not only reduced the fever induced by PGE2-dependent, but also, that induced by PGE2-independent endogenous pyrogens. Moreover, ibuprofen does not affect the hypothalamic synthesis/release of IL-1β and IL-6.