Background/Objectives: Prader–Willi syndrome (PWS) is a rare, genetically determined neurodevelopmental disorder. Individuals with PWS face numerous challenges that significantly impact their psychological well-being and quality of life, ultimately limiting their personal and social functioning. This study aimed to evaluate the quality of life and psychological well-being in a sample of Italian adult patients with PWS compared to an age-matched control group of normal-weight Italian individuals. Methods: Thirty patients with PWS (11 men and 19 women; mean age ± SD: 36.4 ± 10.31 years; mean Body Mass Index (BMI: 35.7 ± 8.92 kg/m2) and thirty Italian adult individuals from the general population (5 men and 25 women; mean age ± SD: 32.1 ± 6.86 years; mean Body Mass Index (BMI: 21.8 ± 2.90 kg/m2) were studied. Quality of life and well-being were assessed using the Italian versions of the 36-item Health Survey Short Form and the Psychological General Well-Being Index. Results: Normal-weight subjects scored significantly higher than PWS patients on the physical health (p < 0.001) and social functioning (p = 0.047) subscales of the SF-36. Conversely, PWS patients scored higher on the vitality subscale (p < 0.001). Similarly, the vitality subscale of the PGWBI was significantly higher in PWS patients than in controls (p = 0.010), whereas the Self-Control subscale of the PGWBI was higher in controls compared to PWS patients, albeit not statistically significant (p = 0.057). Discussion: Patients with PWS exhibited impairments in various aspects of quality of life and psychological well-being, including physical, behavioral, and social domains. However, the higher vitality scores observed in PWS patients suggest a preserved dimension of their psychological well-being. Conclusions: These findings enhance the understanding of the psychological condition of patients with PWS and provide valuable insights for improving multidisciplinary psychological treatment approaches for these individuals.
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