Background. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing quality of life impairments such as insatiable hunger (hyperphagia) and obesity. We explored caregivers’ willingness to assume treatment risk in exchange for reduced hyperphagia according to a PWS-validated observer-reported outcome measure. Methods. We partnered with PWS patient organizations to develop a discrete-choice experiment exploring caregivers’ benefit-risk tradeoffs for emerging PWS treatments. The treatment benefit was a reduction in hyperphagia (as measured by a 0-, 5-, or 10-point change on the Hyperphagia Questionnaire for Clinical Trials [HQ-CT]). Treatment risks included weight gain (none, 5%, 10%), added risk of skin rash (none, 10%, 20%), and risk of liver damage (none, 1 in 1000, 10 in 1000). Preference models were estimated using mixed logistic regression and maximum acceptable risk. We explored differences in preferences across familial caregivers of patients with and without hyperphagia. Results. Four hundred sixty-eight caregivers completed the online survey. The majority of caregivers reported that patients experienced hyperphagia (68%) and half of patients experienced obesity (52%). Caregivers of patients without hyperphagia were willing to accept greater weight gain (16.4% v. 8.1%, P = 0.004) and a higher risk of skin rash (11.7% v. 6.2% P = 0.008) as compared to caregivers of patients with hyperphagia. Caregivers of patients with hyperphagia would accept a higher risk of liver damage as compared to caregivers of patients without hyperphagia (11.9 out of 1000 v. 6.4 out of 1000, P = 0.04). Conclusions. This research demonstrates that caregivers are willing to accept risk in exchange for a five-point improvement on the HQ-CT, a smaller marginal improvement than had been previously classified as meaningful. Patient experience with hyperphagia is a modifier in how much risk caregivers will accept.