Objective: To evaluate the neurobiological changes using fMRI occurring with systematic cognitive rehabilitation (CR) in subjects with traumatic brain injury (TBI) and compare to repeat fMRI in control subjects. Design: Case series. Setting: Outpatient. Participants: Three subjects with a chronic history of TBI and visual scanning and reading deficits and three matched normal controls subjects. Interventions: Weekly CR addressing deficits in visual scanning, visual perception, attention, verbal fluency, and reading. Main outcome measures: Subjects with TBI were examined with neuropsychological and academic testing and fMRI using a sentence reading task prerehabilitation and postrehabilitation. Matched control subjects participated in 2 fMRI sessions, using the identical task. Results: All subjects were more than 80% accurate on the fMRI sentence-reading task. Expected clusters of activation and relative stability across imaging sessions were demonstrated in control subjects. Subjects with TBI demonstrated a greater extent of variability, as defined by novel activation clusters, in their activation pattern across the 2 imaging sessions. Mean number of novel activation areas in the subjects with TBI was 16.6 (12.28) and in controls 9.2 (2.14). When the subjects with TBI activation networks are compared with the control subjects, diverse and excess activation was demonstrated both prerehabilitation and postrehabilitation. All subjects demonstrated significant improvement on neuropsychological testing post-CR. Changes in neuropsychological components of reading could be related to significant alterations in the activation network in response to the fMRI reading task. Conclusions: The increased exposure to visual perceptual exercises, text, and rapid word reading tasks most likely influenced the activation pattern exhibited by the subjects with TBI post-CR. CR may influence existing activation pattern post-TBI by strengthening existing components of the network and promoting development of alternative activation patterns to achieve successful completion of cognitive tasks like sentence reading.