Using positron emission tomography (PET), we studied physiological changes in a patient with frontal lobe damage resulting from closed head injury by assessing his regional cerebral blood flow (rCBF) pattern relative to that of his uninjured monozygotic (MZ) cotwin and against normal variability between cotwins in 10 comparably-aged, uninjured MZ twin pairs. rCBF was measured during the Wisconsin Card Sorting Test (WCST) and a sensorimotor control task. Differences between the index twins in rCBF activation (WCST-control) in regions determined on coplanar MRIs were compared to within-pair differences in the control group using the Z-statistic. Activation differences between the index twins extending beyond normal variability were found in two regions-relative to his uninjured cotwin, the injured twin showed less activation in the inferior portion of the left inferior frontal gyrus while showing greater activation in the left hippocampus (P < 0.04). This pattern contrasts with that of normal subjects during WCST performance of augmented rCBF in the prefrontal cortex and not in the hippocampus. These rCBF differences appear to reflect the utilization of different neural systems when performing a frontal-lobe task. The use of the hippocampus by the injured twin might reflect an attempt to compensate for compromised frontal lobe functioning.