Cholinesterase inhibitors are known to enhance cognitive function among patients with dementia of the Alzheimer's type. It is quite possible that this clinical benefit may extend to other patient groups, yet this issue awaits further exploration. This study examines the use of the cholinesterase inhibitor donepezil in the treatment of patients with a history of brain injury and subsequent cognitive impairment. The sample was comprised of 53 ambulatory psychiatric patients who were receiving care for psychiatric sequelae of brain injury. In this sample, residual cognitive impairment was treated with adjunctive donepezil. This study reports the clinical assessments of this patient sample in outpatient follow-up for up to two years duration. Assessments of cognition with the Wechsler Adult Intelligence Scale-Revised and the Hooper Visual Organization Test were obtained on a subset of this sample (N = 22). Clinician assessment ratings were analyzed for the entire sample. Results indicated an improvement in full-scale IQ (t = 2.5, p = 0.02) score as well as clinician-based ratings (t = 12.2, p < 0.0001). Further research will likely delineate whether specific types of brain injuries are most responsive to cholinesterase inhibitors. These findings suggest that donepezil may enhance clinical response by complementing the medication management of other concomitant psychiatric disturbances related to brain injury.