The aim of this investigation was to elucidate the effect of CPAP withdrawal on neurometabolic and cardiometabolic markers in patients with obstructive sleep apnoea. We evaluated 70 patients (mean age 61±10 years, 82% men) treated with CPAP in two 2-week, parallel, randomised controlled trials. CPAP withdrawal resulted in elevated 3,4-dihydroxyphenylglycol, norepinephrine and cortisol after 2 weeks of CPAP withdrawal; however, no statistically significant changes of the renin–angiotensin–aldosterone system (RAAS) determinants were documented. In summary, CPAP withdrawal may be more prominently linked to short-term increases in sympathetic activation than hypothalamic–pituitary–adrenal axis or RAAS activation. ClinicalTrials.gov Identifier: NCT02493673 and NCT02050425.