Background Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with hypothalamic dysfunction leading to obesity and behavioral disabilities, including eating disorders (EDs). We evaluated the effects of the COVID-19 infection and lockdown on mental and physical health in PWS. At the end of April, 85 adults with PWS completed a self-administered questionnaire, including lockdown conditions, physical activity (PA), ED, and medical and behavioral outcomes. Body weight was measured at home and self-reported. Results Patients (53% women, 45% disomic) were assessed, with a mean age of 28.1±8.7 years and body mass index (BMI) of 37±11 kg/m². Seventy percent lived in the Paris region (France) and were confined with their parents. The mean weight change was 1.0±3.3 kg. We compared patients showing weight loss (n=39, -3.3±2.9 kg) to patients showing weight gain (n=22, +2.3±1.5 kg): the BMI was lower (34.6±9.2 versus 40.4±9.5 kg/m², p=0.02), PA increased (26% versus 5%, p=0.04), and EDs improved (51% versus 14%, p=0.005). Behavioral disorders increased for 13% of the cohort. Three individuals (3.5%) were diagnosed with non-severe COVID-19. Conclusion Lockdown during the COVID-19 pandemic was associated with positive effects for most French adults with PWS, with weight loss probably associated with a more favourable environment during this period. We observed no severe forms of COVID-19.