The inability of neonates to fully evoke the acute-phase reaction to infection is thought to be due in part to central nervous system immaturity. We used the expression of Fos protein to evaluate whether acute-phase reaction deficits in neonates may indeed be linked to unresponsiveness of brain regions that mediate the responses to infection in adult animals. In this study, we used lipopolysaccharide (LPS) as the infectious agent. Rats aged 0–1, 3, 6, 9, 12 and 15 days were divided into groups treated with low- or high-dose LPS (Escherichia coli; 50 and 500 µg/kg, respectively, i.p.) or pyrogen-free saline (PFS) i.p. Two hours after injection, the animals were deeply anesthetized, sacrificed, and their brains removed for Fos immunocytochemistry. Fos-like immunore-active (FLI) neurons in the preoptic area (POA), paraventricular nucleus of the hypothalamus (PVN), and organum vasculosum laminae terminalis (OVLT) were compared between the treatment and the age groups. The fore-brain was devoid of FLI neurons in 1-day-old rats, but FLI neurons were present at 3 days of age and continued to increase with age until 9 days after birth. There were no significant differences between the LPS- and PFS-treated groups until day 12 of age. At 12 and 15 days of age, FLI neurons in the PVN, medial preoptic and lateral preoptic nuclei, and the area surrounding the OVLT were greater in the LPS-treated animals. The expression appeared to be both age- and dose-dependent. These observations show that the rat brain structures that participate in the mediation of the acute-phase reaction do not become responsive to systemic pyrogens until 12 days of age, thus suggesting that insensitivity of the brain to pyrogenic agents may be partly responsible for the poor response of neonates to infectious agents.