Hypoxia causes a regulated decrease in body temperature (T_b), and nitric oxide (NO) is now known to participate in hypoxia-induced hypothermia. Hypoxia also inhibits lipopolysaccharide (LPS)-induced fever. We tested the hypothesis that NO may participate in the hypoxia inhibition of fever. The rectal temperature of awake, unrestrained rats was measured before and after injection of LPS, with or without concomitant exposure to hypoxia, in an experimental group treated with N-nitro-L-arginine (L-NNA) for 4 consecutive days before the experiment and in a saline-treated group (control). L-NNA is a nonspecific NO synthase inhibitor that blocks NO production. LPS caused a dose-dependent typical biphasic rise in T_b that was completely prevented by hypoxia (7% inspired oxygen). L-NNA caused a significant drop in T_b during days 2-4 of treatment. When LPS was injected into L-NNA-treated rats, inhibition of fever was observed. Moreover, the effect of hypoxia during fever was significantly reduced. The data indicate that the NO pathway plays a role in hypoxia inhibition of fever.