Objectives: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-tomoderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS can be difficult for caregivers to cope with and are likely to cause significant and long-term caregiver burden. The current study examined burden in 142 caregivers of children and adults with PWS living in the US using the Zarit Burden Interview (ZBI). The study aimed to measure the level of burden in caregivers of individuals with PWS, to explore the impact of PWS on caregiver quality of life, and to assess ZBI as an indicator of that impact. Results: Caregivers participating in this study were predominantly mothers, 30±59 years old, non-Hispanic Whites, married or in a relationship, with an annual household income slightly distributed towards higher income. Nearly 90% of the caregivers children with PWS lived at home. Caregivers experienced high caregiver burden with an average ZBI score of 44.4 ± 15.4. ZBI scores were highest for caregivers of teenage and young adult individuals with PWS (49.2 ± 14.6 and 49.2 ± 14.1, respectively), while those caring for older adults (>30) and the youngest age group had lower scores (38.6 ±10.5 and 34.8 ±12.5, respectively). Caregivers reported that caring for a person with PWS negatively impacted their romantic relationship, ability to work, sleep, and mood. Whereas we did not find strong correlations between family income or level of help the caregiver receives and ZBI scores, the results showed significant correlations and a linear relationship between ZBI scores and caregiver depressed mood, feelings of anxiety, negative romantic relationship impact, as well as sleep and work disruption. Conclusions: Our study reveals that PWS incurs high caregiver burden and impacts many aspects of the lives of caregiver. We identified the ZBI as a good predictor of that impact. Our findings draw attention to the critical unmet need for support for caregivers of individuals with PWS.