Hyperthermic responses are commonly reported in cases of human medical emergency following recreational use of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), but a precise determination of contributing environmental factors has been elusive given the relative scarcity of threatening and fatal reactions in humans. This study was conducted to determine if elevated physical activity contributes to hyperthermic responses to MDMA in a well controlled animal model. Unrestrained male Wistar rats were monitored with minimally-invasive radiotelemetry techniques following challenge with MDMA (1.0, 5.6 and 10.0 mg/kg, s.c.). Studies were conducted in low (23-25°C) and high (27°C) ambient temperature (TA), with and without access to an activity wheel. The study confirmed dose dependent effects on body temperature, chamber activity and wheel activity which were modified by different TA conditions. Increases in wheel and home chamber activity produced by 10 mg/kg MDMA increased the magnitude of hyperthermia under 27°C TA. Furthermore, greater subject mortality was observed in the wheel-access condition compared with the no-wheel condition. These data provide direct evidence that sustained physical activity increases the hyperthermic response to MDMA and that this is associated with increased lethality. This is the first direct experimental confirmation that increased physical activity may be a risk factor for adverse reactions to MDMA in human user populations.