Fractalkine (CX₃CL1) to fractalkine receptor (CX₃CR1) interactions in the brain are involved in the modulation of microglial activation. Our recent findings indicate that there is microglial hyperactivity in the aged brain during an inflammatory challenge. The underlying cause of this amplified microglial response in the aged brain is unknown. Therefore, the purpose of this study was to determine the degree to which age-associated impairments of CX₃CL1 and CX₃CR1 in the brain contribute to exaggerated microglial activation after intraperitoneal (i.p.) injection of lipopolysaccharide (LPS). Here we show that CX₃CL1 protein was reduced in the brain of aged (18–22mo) BALB/c mice compared to adult (3–6mo) controls. CX₃CL1 protein, however, was unaltered by LPS injection. Next, CX₃CR1 levels were determined in microglia (CD11b⁺/CD45^low) isolated by Percoll density gradient separation at 4 and 24h after LPS injection. Flow cytometric and mRNA analyses of these microglia showed that LPS injection caused a marked decrease of CX₃CR1 and a simultaneous increase of IL-1β at 4h after LPS injection. While surface expression of CX₃CR1 was enhanced on microglia of adult mice by 24h, it was still significantly downregulated on a subset of microglia from aged mice. This protracted reduction of CX₃CR1 corresponded with a delayed recovery from sickness behavior, prolonged IL-1β induction, and decreased TGFß expression in the aged brain. In the last set of studies BV2 microglia were used to determine effect of TGFß on CX₃CR1. These results showed that TGFβ enhanced CX₃CR1 expression and attenuated the LPS-induced increase in IL-1β expression.