BACKGROUND AND PURPOSE: Hyperintense basal ganglia on MR imaging support the diagnosis of sporadic Creutzfeldt-Jakob disease (CJD). Our aim was to study the frequency of patients with sporadic CJD presenting with and without characteristic basal ganglia lesions on MR imaging and to examine the corresponding patient characteristics. MATERIALS AND METHODS: Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted images (DWI) of 55 patients with CJD were assessed for signal-intensity increase (FLAIR) or restricted diffusion (DWI) in 7 cortex regions and the basal ganglia, thalamus, and cerebellum. Patient characteristics as well as electroencephalography, CSF, and codon 129 genotype of the prion protein gene (PRNP) were correlated with the most frequent MR imaging lesion patterns. RESULTS: Two major lesion patterns were identified by DWI: cortex and basal ganglia involvement (two thirds) and isolated cortex involvement (one third). In the latter patient group, the cortex involvement was widespread (at least 3 regions affected in 89% on DWI) and usually included the frontal and parietal lobes (78%). The length of the disease course was significantly prolonged (median, 12 versus 5 months). No significant differences were observed concerning electroencephalography and CSF findings and codon 129 genotype distributions. Of 4 patients with normal MR imaging findings, the CSF was positive for the 14-3-3 protein in 3. CONCLUSION: A high number of patients with CJD present without basal ganglia lesions on MR imaging. Isolated cortex involvement on DWI and FLAIR should lead to suggestion of CJD, even if the disease course is only slowly progressive. Additional 14-3-3 protein analysis in the CSF may support the CJD diagnosis.