© 2016 The Authors Objective To assess medical resource utilization associated with Prader-Willi syndrome (PWS) in the US, hypothesized to be greater relative to a matched control group without PWS. Study design We used a retrospective case-matched control design and longitudinal US administrative claims data (MarketScan) during a 5-year enrollment period (2009-2014). Patients with PWS were identified by Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 759.81. Controls were matched on age, sex, and payer type. Outcomes included total, outpatient, inpatient and prescription costs. Results After matching and application of inclusion/exclusion criteria, we identified 2030 patients with PWS (1161 commercial, 38 Medicare supplemental, and 831 Medicaid). Commercially insured patients with PWS (median age 10 years) had 8.8-times greater total annual direct medical costs than their counterparts without PWS (median age 10 years: median costs $14 907 vs $819; P <.0001; mean costs: $28 712 vs $3246). Outpatient care comprised the largest portion of medical resource utilization for enrollees with and without PWS (median $5605 vs $675; P <.0001; mean $11 032 vs $1804), followed by mean annual inpatient and medication costs, which were $10 879 vs $1015 (P <.001) and $6801 vs $428 (P <.001), respectively. Total annual direct medical costs were ∼42% greater for Medicaid-insured patients with PWS than their commercially insured counterparts, an increase partly explained by claims for Medicaid Waiver day and residential habilitation. Conclusion Direct medical resource utilization was considerably greater among patients with PWS than members without the condition. This study provides a first step toward quantifying the financial burden of PWS posed to individuals, families, and society.