Discriminating Creutzfeldt-Jakob disease (CJD) from dementia with Lewy bodies (DLB) may be clinically difficult to achieve. The authors describe 10 patients with DLB initially referred to the French Network of Human Spongiform Encephalopathies as having suspected CJD. In a series of 465 autopsied cases, DLB ranked second among degenerative alternative diagnoses to CJD. The authors analyzed the factors that contributed to misleading the diagnosis, and suggest that the detection of 14-3-3 protein in CSF may be useful to distinguish CJD from DLB.