Abstract-Obstructive sleep apnea occurs frequently in patients with drug-resistant hypertension. The factors accounting for this observation, however, are unclear. Both conditions demonstrate clinical features suggestive of extracellular fluid volume overload. The aims of this study were to examine whether the spontaneous overnight fluid shift from the legs to the upper body is associated with obstructive sleep apnea in hypertensive subjects and whether its magnitude is greater in drug-resistant hypertension. Leg fluid volume and the circumference of the calf and neck were measured before and after sleep in drug-resistant hypertensive (nϭ25) and controlled hypertensive (nϭ15) subjects undergoing overnight polysomnography. The severity of obstructive sleep apnea was greater in the drug-resistant hypertensive group than in the controlled hypertensive group (apnea-hypopnea index: 43.0Ϯ5.4 versus 18.1Ϯ4.2 events per hour of sleep; Pϭ0.02, case-mix adjusted). In both groups, the apnea-hypopnea index strongly related to the amount of leg fluid volume displaced (R 2 ϭ0.56; PϽ0.0001), although the magnitude of change was greater in the drug-resistant hypertensive group (346.7Ϯ24.1 versus 175.8Ϯ31.3 mL; Pϭ0.01, propensity-score adjusted). The overnight reduction in calf circumference and increase in neck circumference were also greater in drug-resistant hypertension (both PՅ0.02). In hypertensive subjects, rostral fluid displacement strongly relates to the severity of obstructive sleep apnea with its magnitude being greater in drug-resistant hypertension. Our findings support the concept that fluid redistribution centrally during sleep accounts for the high prevalence of obstructive sleep apnea in drug-resistant hypertension. rug-resistant hypertension (DRH) is emerging as a major and growing problem in managing hypertension. It accelerates the atherosclerotic burden of aging and is associated with a significant increased risk of hypertensive target organ damage. 1 In a previous study, we reported that patients with DRH had a very high prevalence of obstructive sleep apnea (OSA) 2 and subsequently demonstrated that treatment of OSA with continuous positive airway pressure was accompanied by a significant fall in both nighttime and daytime blood pressure (BP). 3 Obesity is associated both with decreased responsiveness to antihypertensive medications 4 and with OSA. 5 Whether obesity is the factor that explains the association between DRH and OSA, however, is unclear, because increased body weight and neck girth only account for approximately one third of the variability in the frequency of apneas and hypopneas per hour of sleep (ie, the apneahypopnea index [AHI]). 6 Moreover, the factors accounting for weight-related antihypertensive drug resistance have not been identified.Many studies have demonstrated abnormalities in extracellular fluid volume regulation in DRH and OSA. Plasma renin is generally suppressed in both conditions, 7,8 and primary aldosteronism is a common finding in DRH. 9 BP of DRH patients often falls dr...