ABSTRACT: INTRODUCTION: In this study, we evaluated the activity of the neuroendocrine axes in patients with polymyalgia rheumatica (PMR) before and after tumor necrosis factor (TNF)-α-blocking etanercept treatment, which previously has been shown to reduce interleukin 6 (IL-6) and C-reactive protein (CRP) markedly in PMR. METHODS: Plasma samples were collected from 10 glucocorticoid-naïve patients with PMR and 10 matched controls before and after etanercept treatment (25 mg biweekly for 2 weeks). The primary end points were pre- and posttreatment levels of adrenocorticotropic hormone (ACTH), cortisol, adrenaline, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), prolactin, and insulin-like growth factor 1 (IGF-1). RESULTS: Before TNF-α-blocking treatment, plasma TNF-α, ACTH, and cortisol levels were higher in patients versus controls (P <0.05 and P <0.001, respectively); during TNF-α blockade in patients, levels of both hormones decreased (P <0.05 and P <0.01, respectively), whereas levels in controls increased (P <0.05), abolishing the pretreatment differences. Pretreatment adrenaline levels were more than twice as high in patients than in controls (P <0.01); after treatment in patients, levels had decreased (P <0.05) but remained higher versus controls (P <0.05). Levels of the other hormones never differed significantly between groups (P > 0.05). CONCLUSIONS: In PMR, TNF-α may increase the activities of the hypothalamic-pituitary-adrenal and the hypothalamic-sympthoadrenomedullary axes. Secretion of TSH, FSH, prolactin, and IGF-1 is not clearly changed in PMR. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00524381).