Background: The marked improvement in outcome following induction of hypothermia after cardiac arrest has spurred the search for better methods to induce cooling. A regulated decrease in core temperature mediated by a drug-induced reduction in the set point for thermoregulation may be an ideal means of inducing hypothermia. To this end, the exploratory drug HBN-1 was assessed as a means to induce mild and prolonged hypothermia. Methods: Free moving rats were infused i.v. for 12 hours with: a vehicle at room temperature (normothermia), a vehicle chilled to 4°C (forced hypothermia), or HBN-1 (mixture of ethanol, lidocaine, and vasopressin) at room temperature. Core (intra-abdominal) temperature (T c ) was measured telemetrically, tail skin temperature (T tail ) by infrared thermography, metabolic rate (MR) was estimated with indirect calorimetery, and shivering was scored visually. Results: HBN-1 elicited a reduction in T c from 37.5°C to 34°C within 80 minutes after initiation of the infusion; T c was maintained between 33°C and 34°C for more than 13 hours. HBN-1 infusion was associated with a reduction in MR ( p = 0.0006), a slight reduction in T tail , and no evidence of shivering ( p < 0.001). The forced hypothermia group displayed shivering ( p < 0.001), a significant increase in MR, and a decrease in T tail , indicative of peripheral vasoconstriction to reduce heat loss. Conclusion: HBN-1 infusion induced a mild and prolonged hypothermia in free moving, unanesthetized rats characterized by modulation of thermoeffectors to reduce heat gain and increase heat loss. HBN-1 thus appears to elicit regulated hypothermia and may provide a new method for achieving a prolonged state of therapeutic hypothermia.