Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder. In adults, the syndrome is characterised by muscular hypotonia, a different body composition with more body fat than muscle mass, hyperphagia, behavioural problems, and cognitive dysfunction. Endocrine deficiencies are common, including growth hormone (GH) deficiency. Here, we present data from a cross-sectional study in adults with PWS with a focus on the long-term safety of GH treatment. A total of 22 patients (14 men) were treated with GH for a median of 20 years. Data on body composition, hormones, and metabolic parameters were retrieved from the patients’ medical records. The median age was 27 years. The median GH dose was 0.5 mg/day. Insulin-like growth factor 1 (IGF-I) and blood lipids were normal, while fasting glucose and HbA1c were slightly elevated in three men with diabetes. Fat mass was less than fat free mass in all, though this was less pronounced in women. GH treatment did not negatively affect the metabolic profile, and none developed cardiovascular diseases or cancer. All adults on long-term GH treatment had a normal body composition and our results indicate that treatment was safe. However, PWS is a complex, multisystemic disease and continuous, individual considerations are required during GH treatment, especially in patients with risk factors for adverse effects.