Total tau protein (t-tau) levels in cerebrospinal fluid (CSF) (CSF-tau) are markedly elevated in patients with Creutzfeldt-Jakob disease (CJD). Some CSF-tau may leak into the blood. We evaluated t-tau levels in serum (serum-tau) as a possible marker for the differential diagnosis of CJD from Alzheimer's disease (AD) and other rapidly progressive dementias (RPD). Serum- and CSF-tau levels were determined in patients with sporadic CJD (n = 12), AD (n = 10) and RPD but no CJD (non-CJD-RPD; n = 9) who showed RPD fulfilling the World Health Organization (WHO) criteria for possible CJD at onset and had a final diagnosis other than CJD. We also analyzed serum-tau levels in healthy volunteers as a control group (n = 10). Serum- as well as CSF-tau levels were significantly elevated in CJD group compared to those in AD, non-CJD-RPD and healthy control groups. Serum-tau would be a simple and useful marker to distinguish CJD from AD and non-CJD-RPD, requiring further large study to confirm this.