Acute starvation attenuates the fever response to pathogens in several mammalian species. The underlying mechanisms responsible for this effect are not fully understood, but may involve a compromised immune and/or thermoregulatory function, both of which are prerequisites for fever generation. In the present study, we addressed whether the impaired innate immune response contributes to the reported attenuation of the fever response in fasted rats during lipopolysaccharide (LPS)-induced inflammation. Animals fasted for 48 h exhibited a significant and progressive hypothermia prior to drug treatment. An intraperitoneal injection of LPS (100 µg/kg) resulted in a significantly attenuated fever in the fasted animals when compared to the fed counterparts. This attenuation was accompanied by the diminution in the concentration of some {tumor necrosis factor (TNF) and interleukin (IL)-1 receptor antagonist (IL-1RA)} but not all (IL-1 and IL-6) of the plasma cytokines normally elevated in association with the fever response. Nevertheless, fasting had no effect on the LPS-induced inflammatory responses at the level of the brain as assessed by mRNA expressions of inhibitory factor B, suppressor of cytokine signaling (SOCS) 3, IL-1, cyclooxygenase (COX)-2, and microsomal prostaglandin (PG) E synthase (mPGES)-1 in the hypothalamus, as well as by PGE₂ elevations in the cerebrospinal fluid. In contrast, fasting significantly attenuated the fever response to central PGE₂ injection. These results show that fasting does not alter the febrigenic signaling from the periphery to the brain important for central PGE₂ synthesis, but does affect thermoregulatory mechanisms downstream of and/or independent of central PGE₂ action.