We investigated the effects of methamphetamine (METH) on core body temperature (Tb) and motor activity (MA) with or without exposure to a peripheral immune challenge. Mice were exposed to an escalating METH treatment and then to a METH treatment known to cause neurotoxicity (binge METH treatment). This was followed by a challenge with lipopolysaccharide (LPS). Three days later, METH and saline-treated control groups were challenged with an acute test dose of METH (METH test). Animals exposed to the escalating METH treatment exhibited a significant increase in Tb only after the initial exposure to METH (Day 1) and following the METH test (Day 7). The hyperthermic effect produced by the METH test (Day 7) was reduced in mice previously exposed to combined exposure to binge METH and LPS treatments. The escalating METH treatment produced MA sensitization to the METH test. Animals treated with the binge METH, LPS injection or both treatments combined prevented MA sensitization to the METH test. These findings suggest that induction of peripheral endotoxemia in animals with a history of METH reduced the hyperthermic response to a subsequent challenge with METH.