Stress is known to enhance the abuse of various drugs. Although the effects of chronic stress and the neurotoxicity of methamphetamine (METH) are influenced, in part, by hyperthermia, the role of hyperthermia in the hypothesized stress-induced enhancement of METH-induced dopamine (DA) and serotonin depletions and decreases in vesicular monoamine transporter 2 (VMAT-2) immunoreactivity is unknown. Rats were exposed to 10 days of unpredictable stress and then challenged with METH (7.5 mg/kg, i.p., once every 2 hx4 injections). There were no differences in the extracellular DA concentrations of stressed and non-stressed rats administered METH. Prior exposure to chronic unpredictable stress augmented the acute METH-induced hyperthermia, the decreases in VMAT-2 immunoreactivity, and the depletions of striatal DA and serotonin content. Prevention of enhanced hyperthermia through cooling of chronically stressed rats to levels exhibited by non-stressed but METH-exposed rats blocked the enhanced depletions. This study reports the novel finding that chronic stress enhances METH toxicity through enhanced hyperthermia and suggests that this effect may be mediated by early METH-induced decreases in VMAT-2 immunoreactivity.