Presence of MRI brain abnormalities in patients with Chronic Fatigue Syndrome (CFS) was determined and the profile of MRI abnormalities was compared between 39 CFS patients, 18 with (CFS-Psych) and 21 without (CFS-No Psych) a DSM-III-R Axis I psychiatric diagnosis since illness onset, and 19 healthy, sedentary controls (HC). Two neuroradiologists, blind to group membership, separately read the MR films using a detailed protocol for rating and categorizing abnormal signal changes. When findings were incongruent, the two neuroradiologists met to try to reach consensus, otherwise a third neuroradiologist evaluated the MR images and served as a tie-breaker. The CFS-No Psych group showed a significantly larger number of brain abnormalities on T2 weighted images than the CFS-Psych and HC groups. Cerebral changes in the CFS-No Psych group consisted mostly of small, punctate, subcortical white matter hyperintensities, found predominantly in the frontal lobes. No significant difference was found when both CFS groups were combined and compared to the HC group. The use of stratification techniques is an important strategy in understanding the pathophysiology of CFS. This frontal lobe pathology could explain the more severe cognitive impairment previously reported in this subset of CFS patients.