A highly regulated crosstalk exists between the immune and neuroendocrine systems with the altered immune responses in stress-related disorders being a valid example of this interaction. The Wister Kyoto (WKY) rat is an animal model with a genetic predisposition towards an exaggerated stress response and is used to study disorders such as depression and irritable bowel syndrome (IBS), where stress plays a substantial role. The impact of a lipopolysaccride (LPS) immune challenge has not yet been investigated in this animal model to date. Hence our aim was to assess if the stress susceptible genetic background of the WKY rat was associated with a differential response to an acute immune challenge. Central and peripheral parameters previously shown to be altered by LPS administration were assessed. Under baseline conditions, WKY rats displayed visceral hypersensitivity compared to Sprague Dawley (SD) control rats. However, only SD rats showed an increase in visceral sensitivity following endotoxin administration. The peripheral immune response to the LPS was similar in both strains whilst the central neurochemistry was blunted in the WKY rats. Sickness behaviour was also abrogated in the WKY rats. Taken together, these data indicate that the genetic background of the WKY rat mitigates the response to infection centrally, but not peripherally. This implies that heightened stress-susceptibility in vulnerable populations may compromise the coordinated CNS response to peripheral immune activation.