Background: Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder with symptoms that impact health and quality of life (QOL). There is limited data on global health, QOL and the relationship with mood in individuals with PWS. Methods: Parents completed three validated assessments, the Glasgow Depression Scale-Carer Supplement (GDS-CS), PROMIS Parent-Proxy Global Health 7 and PROMIS Parent-Proxy Life Satisfaction 8b, for 527 individuals with PWS. Results: Mean GDS-CS score was 8.29 (SD 4.55), and 18% had a score of 13+, reflective of possible depression. Mean PROMIS Global Health and Life Satisfaction scores were 41.46 (SD 8.48) and 43.39 (SD 8.48), respectively, and are lower compared to the general population. Both PROMIS scales worsened with age, and scores on the PROMIS and GDS-CS were associated with parent reports of depression for the person with PWS. Conclusions: These validated instruments may be useful for assessing mood and QOL in PWS.