Diagnosis of rapidly progressive dementia (RPD) poses a complex medical challenge that requires an exhaustive evaluation. Although prion diseases, in particular Creutzfeldt-Jakob disease (CJD), are often suspected, many other nonprion diseases may present as RPD. Our aim was to review the causes of RPD in our center to better understand the underlying conditions. We reviewed clinical, neuroimaging, and cerebrospinal fluid data from patients with RPD admitted to our hospital from 1994 to 2009. Forty-nine patients (mean age at onset 72.4 y) with RPD were admitted to our center during the study period. The mean interval between the onset of symptoms and admission was 4.6 months. The final clinical diagnoses were as follows: nonprion neurodegenerative diseases (36.8%), CJD (30.6%), vascular dementia (8.2%), toxic-metabolic conditions (8.2%), and other disorders (16.2%). Among cases with informed death (n = 19), the average survival time was 8.6 ± 9.5 months. Survival was shorter among patients with prion disease (n = 10) than in those with other diagnoses (n = 9, P = 0.004). In conclusion, nonprion neurodegenerative diseases are the most common cause of RPD in our center. Our results suggest that although CJD is often suspected as a cause of RPD, its frequency depends on the referral differences across specialized centers.