OBJECTIVES: Antipsychotics are routinely administered to patients with traumatic brain injury, even though the benefits vs. risks of this approach on behavioral recovery are unclear. To clarify the issue, the present study evaluated the effect of single and multiple administrations of haloperidol and risperidone on functional outcome after traumatic brain injury. DESIGN: Prospective and randomized study in rodents. SETTING: Experimental research laboratory at the University of Pittsburgh. SUBJECTS: A total of 60 adult male Sprague-Dawley rats weighing 300-325 g. INTERVENTIONS: Anesthetized rats received either a cortical impact or sham injury and then were randomly assigned to five traumatic brain injury groups (0.045 mg/kg, 0.45 mg/kg, or 4.5 mg/kg risperidone; 0.5 mg/kg haloperidol; or 1 mL/kg vehicle) or three sham groups (4.5 mg/kg risperidone, 0.5 mg/kg haloperidol, or 1 mL/kg vehicle). The experiment consisted of three phases. In the first phase, a single treatment was provided (intraperitoneally) 24 hrs after surgery, and motor and cognitive function was assessed on postoperative days 1-5 and 14-18, respectively. During the second phase, after completion of the initial behavioral tasks, the same rats were treated once daily for 5 days and behavior was reevaluated. During the third phase, treatments were discontinued, and 3 days later, the rats were assessed one final time. MEASUREMENTS AND MAIN RESULTS: Time (seconds) to maintain beam balance, traverse an elevated beam, and to locate a submerged platform in a Morris water maze was recorded. Neither motor nor cognitive performance was affected after a single treatment, regardless of group assignment (p > .05). In contrast, both behavioral deficits reoccurred after daily treatments of risperidone (4.5 mg/kg) and haloperidol (p < .05). The cognitive deficits persisted even after a 3-day washout period during the third phase. CONCLUSIONS: These data suggest that although single or multiple low doses of risperidone and haloperidol may be innocuous to subsequent recovery after traumatic brain injury, chronic high-dose treatments are detrimental.