Objectives: Prader-Willi syndrome (PWS) is a rare genetic disorder associated with varying degrees of hyperphagia, obesity, intellectual disability, and anxiety across the affected individuals’ lifetimes. This study quantified caregiver priorities for potential treatment endpoints to identify unmet needs in PWS. Methods: The authors partnered with the International Consortium to Advance Clinical Trials for PWS (PWS-CTC) and a diverse stakeholder advisory board to develop a best–worst scaling instrument. Seven relevant endpoints were assessed using a balanced incomplete block design. Caregivers were asked to determine the most and least important of a sub-set of four endpoints in each task. Caregivers were recruited nationally though patient registries, email lists, and social media. Best–worst score was calculated to determine caregiver priorities; ranging from 0 (least important) to 10 (most important). A novel kernel-smoothing approach was used to analyze caregiver endpoint priority variations with relation to age of the PWS individual. Results: In total, 457 caregivers participated in the study. Respondents were mostly parents (97%), females (83%), and Caucasian (87%) who cared for a PWS individual ranging from 4–54 years. Caregivers value treatments addressing hyperphagia (score = 7.08, SE = 0.17) and anxiety (score = 6.35, SE = 0.16) as most important. Key variations in priorities were observed across age, including treatments targeting anxiety, temper outbursts, and intellectual functions. Conclusions: This study demonstrates that caregivers prioritize hyperphagia and, using a novel method, demonstrates that this is independent of the age of the person with PWS. This is even the case for parents of young children who have yet to experience hyperphagia, indicating that these results are not subject to a hypothetical bias.