Context: Increased activities of the arginine-vasopressin (AVP) system and the hypothalamic-pituitary adrenal (HPA) axis were shown to be associated with human obesity, but relationships between these systems in obesity remain unclear. Objectives: To assess HPA axis responsiveness and its relation to serum concentrations of the AVP-surrogate copeptin in subjects with obesity (OB) in comparison to non-obesity controls (NOC). Methods: In a cross-sectional monocentric study, thirty-nine OB (f/m 25/14; age 36.5 +/- 10.0 years; body mass index, BMI, 41.5 +/- 4.7 kg/m(2)) were compared to twenty-two NOC 12/10; age 35.3 +/- 8.5 years; BMI 23.1 +/- 2.4 kg/m(2)), matched for age and sex. All individuals underwent the combined dexamethasone/CRH test. Main outcome measures: Plasma ACTH and cortisol curve indicators derived from the dex/CRH test (post-CRH concentrations 30 min after 100 mu g CRH; maximum concentration, MAX; area-under-the-curve, AUC; ACTH/cortisol ratios). Copeptin was assessed in 1500 h samples of the dex/CRH test (after 1.5 mg of oral dexamethasone, prior to CRH administration). Results: Copeptin serum concentrations were higher in OB (median [IQR]: OB 4.62 [2.60-5.88] vs. NOC 3.04 [2.52-4.29] pmol/1, P=0.04). Correspondingly, OB showed higher post-CRH cortisol concentrations (OB: 51.5 [25.9-159.3] vs. NOC: 28.6 [20.0-41.6] nmol/1, P = 0.01) and a lower post-CRH ACTH/cortisol ratio (OB: 0.028 [0.016-0.053] vs. NOC: 0.048 [0.034-0.070] pmol/nmol, P < 0.01). Serum copeptin was significantly associated with HPA responsiveness in OB (post-CRH ACTH: R = 0.42, P < 0.01), driven by OB men (post-CRH ACTH: R=0.76, P < 0.01, post-CRH cortisol: R=0.64, P=0.02). All associations withstand adjustments for BMI and age. Conclusions: The association between increased copeptin with ACTH and cortisol release suggests a potential mechanistic interaction of the AVP system with HPA activation in human obesity. The relation of copeptin and HPA responsiveness should be further validated in situations with pronounced HPA activation, such as depression or multiple sclerosis. (C) 2017 Elsevier Ltd. All rights reserved.