Abstract In elderly individuals high levels of interleukin-1β (IL-1β) in the brain have been implicated in infection-related behavioral pathologies but this has not been directly tested. Therefore, the current study investigated if sickness behavior in aged animals elicited by peripheral injection of lipopolysaccharide (LPS) is mediated through central IL-1β. Adult and aged mice were injected intracerebroventricularly with either saline or IL-1ra (4 μg) immediately prior to intraperitoneal administration of saline or LPS (10 μg) and locomotor and social behaviors were assessed. As anticipated, LPS depressed locomotor activity and social behavior in both adult and aged mice but the behavioral deficits were markedly greater in the aged at 24 h. Pretreatment with IL-1ra did not affect LPS-induced sickness behavior in adults; however, in aged mice IL-1ra attenuated LPS-induced sickness behavior, restoring it to the level exhibited by young adults. Twenty-four hours post-injection hippocampal and hypothalamic tissues were collected to determine IL-1β mRNA expression. Neither LPS nor IL-1ra affected IL-1β mRNA levels in adults, presumably because any effect of LPS had dissipated by 24 h. In contrast, IL-1β mRNA was markedly higher in aged mice 24 h after LPS, and prior treatment with IL-1ra either blocked or attenuated this effect in the hippocampus and hypothalamus, respectively. Taken together these data provide the first direct evidence that central IL-1β is responsible for the severe sickness behavior observed in aged animals after LPS treatment. Thus, inhibiting the central actions of IL-1β may be useful for minimizing behavioral complications in older individuals with an infection.