Numerous preclinical studies have demonstrated that posttraumatic treatment of spinal cord injury (SCI) with thyrotropin-releasing hormone (TRH) or TRH analogs improves long-term behavioral recovery. The purpose of the present study is to provide preliminary data regarding the safety and potential efficacy of TRH in patients with acute SCI. A total of 20 patients with SCI were classified by clinical examination into complete and incomplete injury groups within 12 h of trauma and randomly assigned in double-blinded fashion to treatment with either TRH (0.2 mg/kg intravenous bolus followed by 0.2 mg/kg/h infusion over 6 h) or vehicle (equal volume physiological saline) placebo. A variety of physiological variables were followed during treatment. Clinical examination included motor and sensory testing, as well as assigning a Sunnybrook score based upon level of function. Patients were examined at 24 h, 72 h, 1 week, 1 month, 4 months, and 12 months after injury. TRH infusions were well tolerated. There appeared to be no discernible treatment effect in patients with complete injuries although data were available from only six such patients at 4 months. For the incomplete injury group, a total of 6 treated and 5 placebo patients had 4-month evaluations. TRH treatment was associated with significantly higher motor, sensory, and Sunnybrook scores than placebo treatment. Because of patients lost to subsequent follow-up, 12-month data were not highly informative. These observations must be interpreted with considerable caution because of the small patient numbers, but together with extensive animal studies they support the need for a larger multicenter clinical trial of TRH.