Creutzfeldt-Jakob Disease (CJD) is characterized by bilateral basal ganglia hyperintensities on T2W and diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) scans, consistent with its extrapyramidal neurological manifestations. MRI is diagnostically uninformative about the cerebellar symptoms, equally prominent in CJD. This study was undertaken to explain this apparent paradox. Eleven CJD patients with definite cerebellar or brain stem symptoms were selected from a large prospective study, as well as 11 healthy controls matched for age and gender. All subjects participated in a standardized MRI protocol, including SPGR, fluid-attenuated inversion recovery (FLAIR), DWI and diffusion tensor imaging (DTI). All subjects underwent detailed examination by a neurologist blinded to the radiological findings, who predicted the expected site of cerebral abnormalities. MRI showed good sensitivity for the abnormalities predicted in the cortex (80-90%) and basal ganglia (100%). None of the standard MRI sequences, including DWI, DTI, and FLAIR, revealed any tissue abnormalities in cerebellum or brain stem. Apparent diffusion coefficient (ADC) values, however, were substantially and significantly elevated in several cerebellar structures, where also the volumetric (VBM) analysis revealed elevated cerebrospinal fluid volume, suggesting focal cerebellar atrophy in these CJD patients. In patients with CJD, DWI appears sensitive to the reduced diffusivity in cortex and basal ganglia but insensitive to cerebellar involvement. We propose that the radiological hallmark of cerebellar pathology in CJD is atrophy, revealed quantitatively by both VBM and elevated diffusivity, which is identifiable on ADC maps but poorly visualized in nonquantitative DWI images.