BACKGROUND AND PURPOSE - Mild hypothermia confers profound neuroprotection in ischemia. We recently discovered 2 natural derivatives of thyroxine, 3-iodothyronamine (T1AM) and thyronamine (T0AM), that when administered to rodents lower body temperature for several hours without induction of a compensatory homeostatic response. We tested whether T1AM- and T0AM-induced hypothermia protects against brain injury from experimental stroke. METHODS - We tested T1AM and T0AM 1 hour after and 2 days before stroke in a mouse model of focal ischemia. To determine whether T1AM and T0AM require hypothermia to protect against stroke injury, the induction of hypothermia was prevented. RESULTS - T1AM and T0AM administration reduced body temperature from 37°C to 31°C. Mice given T1AM or T0AM after the ischemic period had significantly smaller infarcts compared with controls. Mice preconditioned with T1AM before ischemia displayed significantly smaller infarcts compared with controls. Pre- and postischemia treatments required the induction of hypothermia. T1AM and T0AM treatment in vitro failed to confer neuroprotection against ischemia. CONCLUSIONS - T1AM and T0AM, are potent neuroprotectants in acute stroke and T1AM can be used as antecedent treatment to induce neuroprotection against subsequent ischemia. Hypothermia induced by T1AM and T0AM may underlie neuroprotection. T1AM and T0AM offer promise as treatments for brain injury.