Background: Surgical instruments used in patients with prion disease must be decontaminated or decommissioned to prevent iatrogenic transmission. This is only done when the diagnosis of prion disease is known. To assess the potential for iatrogenic transmission, we determined the prevalence of surgeries and use of precautions in patients with prion disease at two academic medical centers. Methods: Clinical details, results of investigations, and surgical interventions (performed within one-year of symptom onset) were extracted for patients with probable/definite prion disease at Mayo Clinic (n=107; 1-2014 to 12-2020) and Washington University School of Medicine (n=14; 2-2015 to 12-2019). Results: Twenty-six patients (21.5%) underwent 32 procedures, including 2 high-risk procedures involving the brain. Most procedures (17/32, 53%) occurred in the 1-year period preceding the onset of symptoms attributed to CJD. History of arthritis (OR: 7.4, 95%CI: 1.05-51.8), lack of behavioral symptoms (OR: 3.0, 95%CI 0.97-9.1), and greater time (months) from symptom onset to first MRI (OR: 1.1, 95%CI 1.03-1.2) were independently associated with odds of undergoing an invasive procedure. Prion disease precautions were observed in one case (diagnostic brain biopsy). Conclusions: Procedures were common in patients with diagnosis of prion disease; precautions were not. Coordinated approaches to screening and reporting are needed to prevent iatrogenic transmission.