A mild immune challenge experienced during the neonatal period leads to attenuated febrile responses to a similar challenge experienced later in life. However, the immune response to an endotoxin differs depending upon the severity of the challenge and it is not clear whether a neonatal immune challenge will also affect responses to a severe, potentially life-threatening stimulus, such as sepsis. In the present study, we examined the effects of a neonatal immune challenge with lipopolysaccharide (LPS) on adult sickness responses, as well as the development of endotoxin tolerance, to a septic dose (1 or 3 mg/kg) of the same LPS in male and female rats. We demonstrate significant differences, particularly in males, in the fever profiles of neonatally LPS-treated rats compared to neonatally saline-treated controls. Specifically, male rats treated neonatally with LPS have reduced hypothermic and enhanced hyperthermic responses to both septic doses of LPS in adulthood. A somewhat different profile is seen in females, with neonatally LPS-treated females having reduced hypothermia and enhanced hyperthermia compared to controls with 1 mg/kg but no differences with 3 mg/kg LPS. The results obtained demonstrate that alterations in innate immune responses previously reported for low doses of LPS can, for the most part, also be observed after severe immune challenge in later life.