To report the incidence of prion disease in the United States.

Prion disease decedents were retrospectively identified from the US national multiple cause-of-death data for 2003–2015 and matched with decedents in the National Prion Disease Pathology Surveillance Center (NPDPSC) database through comparison of demographic variables. NPDPSC decedents with neuropathologic or genetic test results positive for prion disease for whom no match was found in the multiple cause-of-death data were added as cases for incidence calculations; those with cause-of-death data indicating prion disease but with negative neuropathology results were removed. Age-specific and age-adjusted average annual incidence rates were then calculated.

A total of 5,212 decedents were identified as having prion disease, for an age-adjusted average annual incidence of 1.2 cases per million population (range 1.0 per million [2004 and 2006] to 1.4 per million [2013]). The median age at death was 67 years. Ten decedents were <30 years of age (average annual incidence of 6.2 per billion); only 2 of these very young cases were sporadic forms of prion disease. Average annual incidence among those ≥65 years of age was 5.9 per million.

Prion disease incidence can be estimated by augmenting mortality data with the results of neuropathologic and genetic testing. Cases <30 years of age were extremely rare, and most could be attributed to exogenous factors or the presence of a genetic mutation. Continued vigilance for prion diseases in all age groups remains prudent.