Background: Recombinant human growth hormone (rhGH) replacement is advocated in adult growth hormonedeficient (GHD) patients to increase bone mass and improve lipid profile, body composition, and quality of life. The long-term effects of discontinuation of rhGh replacement are unknown. Methods: This cohort study and systematic review aim to evaluate the long-term metabolic effects of discontinuation of rhGh replacement in adult GHD patients, with a subgroup analyses according to age (< or > 60 years). Data on anthropometry, lipids, glucose, and bone mass density (BMD) were assessed for 3 years after discontinuation. Results: Cohort study included 64 patients who had discontinued rhGh replacement for >12 months. Fat percentage increased from 31.5 ± 9.5% to 33.8 ± 9.0% (mean difference 2.3, P = 0.003). BMI decreased only in subjects <60 years (P = 0.014). Glucose, total cholesterol, and LDL-cholesterol levels did not change; however, the percentage of patients on statins increased slightly from 39% to 44%. HDL-C concentration increased only in patients <60 years (mean difference 0.2, P = 0.043). Lumbar spine BMD did not change; however, femoral neck BMD and bone turnover markers decreased in subjects <60 years (P = 0.001). Systematic review included eight studies (n = 166 patients) with a follow-up duration of 6-18 months. Of the eight studies, three qualified as low risk of bias and five as having an intermediate risk of bias. None of the studies reported handling of statins, bisphosphonates, and glucose-lowering medication or excluded patients using these medications. Conclusions: In this study, discontinuation of rhGh replacement resulted in metabolic changes only in patients <60 years after 3 years. Further research warrants to determine the optimal strategies for (dis)continuation of rhGh replacement in adult patients with GHD.