Fabry disease is an X-linked disorder associated with early onset stroke. We previously found a significantly elevated cerebral blood flow (CBF) in patients with Fabry disease. We set to determine whether elevated resting CBF in Fabry disease is primarily a cerebrovascular abnormality or is secondary to enhanced neuronal metabolism. The relationship of cerebral metabolism and blood flow to Fabry leukoencephalopathy was also investigated. We measured the global and regional cerebral metabolic rate of glucose using 18-fluoro-deoxyglucose (FDG) and PET in 16 patients with Fabry disease (7 patients with leukoaraiotic lesions and 9 without) and in 7 control subjects. MRI fluid attenuated inversion recovery (FLAIR) studies were also performed in the patient and control groups. All control subjects had normal MRI FLAIR studies with no high-signal deep white matter lesions (WML). Patients were partitioned into FLAIR lesion and non-FLAIR lesion groups. We found no evidence of cerebral glucose hypermetabolism in Fabry disease. On the contrary, significantly decreased regional cerebral glucose metabolism (rCMRGlu) was found particularly in the deep white matter in the Fabry non-lesion group and exacerbated in the lesion group. Lesion-susceptible regions were relatively hyperperfused in non-lesion patients compared to the control group. We conclude that the elevated rCBF and decreased white matter rCMRGlu indicates a dissociation between metabolism and blood flow suggesting chronic deep white matter metabolic insufficiency.