To investigate the relation of arachidonate metabolism to the induction of fever by interleukin-1, indomethacin was administered in either an intracerebroventricular (icv) or a subcutaneous (sc) route in conscious rabbits. Fever induced by icv administration of recombinant human interleukin-1 beta (rhIL-1 beta) was depressed by either icv or sc pretreatment with indomethacin. Fever induced by intravenous (iv) administration of rhIL-1 beta was significantly inhibited, though initial small increase in colonic temperature still remained, and was completely depressed by combination of icv and sc pretreatment with indomethacin. Intracerebroventricularly administered recombinant rabbit IL-1 beta (rrIL-1 beta) induced dose-dependent increases in colonic temperature, which was depressed by sc pretreatment with indomethacin. There is little species specificity between human and rabbit IL-1 beta, in terms of the pyrogenic potency and the inhibitory effect of sc indomethacin on fever induced by icv IL-1 beta. Further, fever caused by icv administration of sodium arachidonate was significantly depressed by sc pretreatment with indomethacin. These results show that the inhibitory effect of indomethacin, administered either icv or sc, on IL-1 beta-induced fever is similar to that of IL-1 alpha-induced fever reported previously. This suggests that the site of arachidonate metabolism significantly involved in the mechanism of fever induction by IL-1 is easily accessible to the brain from the blood.