Abstract Prader-Willi syndrome (PWS) is a complex developmental genetic disorder associated with hypotonia, poor feeding in neonates, onset of hyperphagia in early childhood, and shorter overall life expectancy. Prior epidemiology studies of PWS have examined smaller populations, with limited research in a US population. The aim of this study was to provide a contemporary estimate of PWS prevalence and annual all-cause mortality in the US using a large administrative medical claims dataset. Methods: PWS patients were identified between 2012-2014 via the presence of ≥2 claims with a diagnosis code for PWS on medical claims provided by IQVIA™ Health Plan Claims Data and CMS Medicare fee-for-service claims. Patients were grouped into age bands including: 0-2, 3-8, 9-17, 18-26, 27-49, and ≥50. PWS prevalence and mortality rates were calculated for 2014, then 2018 US census data was used to project rates for the total US population. The presence of select diagnoses and procedures suggestive of a life-threatening event (e.g., mechanical ventilation) with a patient’s prompt disenrollment defined as death in the IQVIA data; vital status is indicated in Medicare data. Results: Overall US diagnosed PWS prevalence was 2.7 per 100k persons (or 1 per 37,037), a prevalence of 8,870 patients in the US in 2018. Diagnosed PWS prevalence 3.9, 5.2, 4.5, 4.2, 2.5, and 1.1 per 100k persons respectively for age bands 0-2, 3-8, 9-17, 18-26, 27-49, and ≥50. The median age of PWS patients was 21 years. The mortality rate was highest among diagnosed PWS patients aged 0-2 years and lowest among those aged 9-17 years and the overall mortality rate was 2.7%. For all respective age bands 0-2, 3-8, 9-17, 18-26, 27-49, and ≥50, the all-cause mortality rate was 5.4%, 3.0%, 1.4%, 2.1%, 2.4%, and 4.5%. The observed median age of death was 23 years (IQR 6-36) Conclusions: The diagnosed PWS prevalence of 1 per 37,037 persons estimated for the 2018 US population is comparable to the other reported US prevalence estimate. As the current study describes diagnosed patients, it likely represents a lower bound of true PWS prevalence. Annual PWS mortality is ≥3 times higher than the overall US population (2.7% vs 0.8%). This rate appears unchanged from mortality estimates reported for PWS populations in the last several decades despite significant advances in genetic testing and the availability of growth hormone therapies in the US. Aggressive management of serious comorbid conditions, especially in younger PWS patients, should be a clinical priority.