The usual clinical profile of Creutzfeldt-Jakob disease (CJD) is that of subacute dementia and intractable myoclonus. Occasionally, some cases present peculiar clinical features. We report on a case of CJD with an unilateral onset showing remarkable neuroimaging features. The patient, aged 72 years, began to suffer from sudden anomia, initially restricted to persons; but in a few weeks it evolved into a global aphasia, right hemiparesis, severe gait disorder, and finally akinetic mutism and intractable myoclonus. He died 11 weeks after onset. Early in the course, an analysis of 14-3-3 protein in CSF was positive. In advanced disease, the EEG showed the typical periodic activity of CJD. FLAIR MRI study showed a mesencephalic and focal cortical hyperintensity. Autopsy was performed and confirmed the diagnosis of CJD with an extensive presence of generalised spongiosis in cerebral grey matter. This case illustrates the usefulness of the life recent paraclinical methods to diagnose CJD in life. New MRI techniques seems to be particularly relevant, as they are not limited to exclude other conditions but can also offer data with validity to a positive diagnosis, like grey matter hyperintensity, that in this case was present also in the midbrain.