The coincidental behavioral and physiological responses to inflammatory stimuli administered either peripherally or centrally were evaluated. In the first study, twenty castrated male pigs were injected ip with 0, 0.5, 5, or 50 μg/kg BW lipopolysaccharide (LPS). Body temperature was monitored telemetrically, and serial blood samples were collected via an indwelling jugular catheter for determination of plasma cortisol and tumor necrosis factor-α (TNF-α) concentrations. Sickness behaviors were measured during 10-min tests at 0, 2, 4, 8, 12, and 24 h post injection. The 5 and 50 μg/kg doses of LPS increased plasma concentrations of cortisol and TNF-α, while inducing anorexia, hypersomnia, and fever. In contrast, although 0.5 μg/kg LPS induced acute anorexia, hypersomnia, and fever, it did not increase plasma TNF-α; and the cortisol response was small and transient, suggesting the behavioral system in pigs is more responsive to LPS than the hypothalamic-pituitary-adrenal (HPA) axis. Because LPS-induced behavior and activation of the HPA axis involve proinflammatory cytokines in the brain, in a second study, unrestrained pigs with jugular catheters were injected intracerebroventricularly (ICV) with recombinant porcine TNF-α. Vehicle or TNF-α (0, 5, or 50 ng/kg) was injected ICV, and plasma cortisol and behavior were determined as before. Pigs injected ICV with 50 ng/kg TNF-α showed anorexia, hypersomnia, and an abrupt increase in plasma cortisol concentration. Whereas 5 ng/kg TNF-α ICV also induced marked sickness behavior, it failed to stimulate the HPA axis, as indicated by plasma cortisol levels. That there was a distinct difference in the magnitude of behavioral and endocrine responses to LPS and TNF-α suggests that different systems that are responsive to inflammatory stimuli exhibit different sensitivities.