Cerebral micro- and macro-vasculopathy have been described in Fabry disease (FD). Neuronal globotriaosylceramide accumulation in selective cortical and brain stem areas including the hippocampus has been reported by autopsy studies in FD, but clinical surrogates as well as the clinical relevance of these findings have not been investigated so far. We measured the hippocampus volumes in a group of clinically affected patients with FD and correlated the findings with the cognitive performance of the patients. Hippocampal volumes were determined manually on T1-weighted MR-images of 25 FD patients (age 36.5 ± 11.0 years) and 20 age-matched controls. Additionally, individual white matter (WM) and gray matter (GM) volumes were measured using brain segmentation analyses. After controlling for age, white matter lesion (WML) volume, and WM/GM-volumes hippocampal volumes were significantly decreased in FD. These findings were substantially more pronounced in a subgroup of men with FD. WM and WM/GM volumes, and memory function did not significantly differ between patients and controls. In patients with FD hippocampal volumes were neither significantly correlated to WML volume nor to WM or WM/GM volumes. Hippocampus atrophy was not driven by the WML or other brain tissue atrophy and seems to correlate with the neuronal involvement in FD. In this young to middle-aged Fabry cohort the hippocampus degeneration was functionally compensated without memory impairment. Longitudinal studies are needed to determine whether this degenerative component in FD will progress and, in concert with the individual WML-load, predict subsequent cognitive decline.