Objective: Isolated GH deficiency (IGHD) could provide a model to investigate the influence of GH deficiency per se and the effect of GH replacement therapy without the influence from other pituitary hormone deficiencies or their treatment. The aim of this study is to address the questions about differences between IGHD and multiple pituitary hormone deficiencies (MPHDs) in clinical presentation and in responsiveness to GH treatment. Design: A nationwide surveillance study was carried out to describe the difference in the clinical presentation and responsiveness to GH treatment of patients with IGHD and MPHDs. Methods: The Dutch National Registry of GH Treatment in Adults was founded in 1998 to gain more insight into long-term efficacy and safety of GH therapy. Out of 2891 enrolled patients, 266 patients with IGHD at the start of GH treatment were identified and compared with 310 patients with MPHDs. Cardiovascular indices will be investigated at baseline and during long-term follow-up, including body composition, lipid profile, glucose metabolism, blood pressure, and morbidity. Results: Patients with IGHD and MPHDs were demonstrated to be different entities at clinical presentation. Metabolically, patients with MPHDs had a larger waist circumference, lower HDL cholesterol level, and higher triglyceride level. The effect of GH treatment was comparable between patient groups. GH seems to protect against rising lipid levels and blood pressure, even after excluding patients using corresponding concomitant medication. The risk for cardiovascular disease or diabetes mellitus during follow-up was not different between patients with IGHD and MPHDs. Conclusions: Patients with IGHD had a less impaired metabolic profile than patients with MPHDs at baseline. Influence of other pituitary hormone replacement therapies on the effect of GH treatment is not demonstrated. © 2014 European Society of Endocrinology.