BACKGROUND In patients with resistant hypertension (RH) and obstructive sleep apnea (OSA), the blood pressure response to continuous positive airway pressure (CPAP) treatment is highly variable and could be associated with differential micro–ribonucleic acid (miRNA) profiles. Currently, no available methods exist to identify patients who will respond favorably to CPAP treatment. OBJECTIVES The aim of this study was to identify plasma miRNA profiles that predict blood pressure responses to CPAP treatment. METHODS Cardiovascular system–focused circulating miRNA expression was evaluated in plasma samples using an 84-miRNA array among patients with RH and OSA at baseline and after 3 months of adherent CPAP use. Pathway analysis and miRNA target gene enrichment were performed in silico. Plasma levels of peptides and hormones related to cardiovascular function were also measured. RESULTS The OSA responder group exhibited blood pressure decreases exceeding the observed median (>4.5 mm Hg) after CPAP, which were not present in the nonresponder group (#4.5 mm Hg) (p < 0.01). Three miRNAs provided a discriminatory predictive model for such a favorable blood pressure response to CPAP (area under the curve: 0.92; p ¼ 0.01). Additionally, CPAP treatment significantly altered a total of 47 plasma miRNAs and decreased aldosteroneto- renin ratios in the responder group (p ¼ 0.016) but not in the nonresponder group. CONCLUSIONS A singular pre-CPAP treatment cluster of 3 plasma miRNAs predicts blood pressure responses to CPAP treatment in patients with RH and OSA. CPAP treatment is accompanied by changes in cardiovascular system–related miRNAs that may potentially influence the risk for cardiovascular disease among patients with OSA and RH. (Effect of Continuous Positive Airway Pressure [CPAP] Treatment in the Control of Refractory Hypertension; NCT00616265) (J Am Coll Cardiol 2015;66:1023–32) © 2015 by the American College of Cardiology Foundation.