Rapidly progressive dementia (RPD) is a rare presentation of different neurological disorders characterized by cognitive impairment leading to loss of functional independence within 24 months or less. The increasing recognition of treatable non-prion causes of RPD has made the differential diagnosis with sporadic Creutzfeldt-Jakob disease (sCJD) of crucial importance. We therefore assessed the frequency of different etiologies of RPD and evaluated the accuracy of newly proposed diagnostic criteria for sCJD. Clinical records of patients with RPD referred to Memory Clinic between 2007 and 2012 were retrospectively analyzed. The accuracy of diagnostic criteria for sCJD was evaluated by: a) MRI images in DWI and FLAIR sequences; and (b) CSF 14-3-3 protein. In addition, CSF total tau protein level was also assessed. Final diagnosis was obtained after a 1-year follow-up or after autopsy. Among 37 patients with RPD, the most frequent causes were non-prion diseases, either untreatable (38%) or potentially treatable (32%), thus leaving sCJD as a less frequent cause (30%). DWI images had a sensitivity of 73% and specificity of 96%, while FLAIR yielded a very low sensitivity (40%). CSF 14-3-3 protein had a sensitivity of 100%, but a very low specificity (43%). The strongest independent predictor of sCJD diagnosis was the CSF tau level (p = 0.002) (91% sensitivity, 83% specificity). Treatable causes of RPD are as frequent as sCJD and a rapid differential diagnosis is mandatory. We suggest that DWI images and CSF analysis combining 14-3-3 and total tau protein determination hold the best informative diagnostic values.