Growth hormone (GH) has been approved for children with Prader-Willi syndrome (PWS) and significantly improves body composition in adults with PWS. Adults with PWS are predisposed to develop impaired glucose tolerance (IGT) and diabetes mellitus type 2 (DMT2). Continuation of GH maintains body composition, but GH is known to induce insulin resistance, which might affect glucose homeostasis. Long-term effects of GH treatment in adults are very limited.To investigate effects of 3 years of GH treatment on glucose homeostasis and prevalence of metabolic syndrome (MS) in adults with PWS.Open-label, prospective study.43 young adults with PWS.Dutch PWS Reference Center.glucose and insulin during oral glucose tolerance test.Estimated mean (95% CI) fasting glucose and insulin levels remained stable during 3 years of GH treatment. Glucose being 4.6 (4.4 to 4.8) mmol/l at start and 4.7 (4.6 to 4.9) mmol/l after 3 years (p=0.07); insulin being 59.5 (45.2 to 75.8) pmol/l and 56.7 (45.2 to 69.6) pmol/l resp. (p=0.72). Sex, ethnicity and fat mass percentage were significantly associated with fasting glucose levels, while IGF-I or GH-dose were not. Blood pressure, lipids and prevalence of MS remained stable during 3 years of GH. IGT prevalence was variable over time, six patients had IGT at start and eleven after 3 years of GH. One patient developed DMT2. However, prevalence of IGT or DMT2 was not significantly higher after 3 years than at study start.3 years of GH treatment in adults with PWS does not impair glucose homeostasis and does not lead to an increased prevalence of DMT2.