Prader-Willi Syndrome (PWS) is a multi-system genetically determined neurodevelopmental disorder and the commonest cause of syndromal obesity. The development of hyperphagia in early childhood is part of the phenotype arising as a result of an impaired neural response to food intake and the inability to regulate food intake in line with energy needs. Severe obesity develops if access to food is not controlled. In this review we evaluate the evidence for increased morbidity and mortality in PWS in order to establish the extent to which it is directly related to the obesity; a consequence of the eating behaviour itself independent of obesity; or associated with other characteristics of the syndrome. Medline, Cochrane, PsychINFO, CINAHL, Web of Science and Scopus databases were used to systematically identify published material on PWS and hyperphagia and syndrome-related morbidity and mortality. One hundred and ten key papers were selected. Data on 500 people with PWS indicated that the average age of death was 21 years and obesity was, as expected, a significant factor. However, the behaviour of hyperphagia itself, independent of obesity, was also important, associated with choking, gastric rupture, and/or respiratory illness. Other syndrome-related factors increased the risk for, and seriousness of, co-morbid illness or accidents. We conclude that improving life-expectancy largely depends on managing the immediate non-obesity and obesity-related consequences of the hyperphagia, through improved support. The development of new treatments that significantly reduce the drive to eat are likely to decrease morbidity and mortality improving quality of life and life expectancy.