Background: Sleep-disordered breathing, predominantly obstructive sleep apnea (OSA), is highly prevalent in patients with hypertension. OSA may underlie the progression to resistant hypertension, partly due to increased activation of the sympathetic nervous system. This analysis of patients with and without OSA evaluated the blood pressure (BP)-lowering effect of sympathetic modulation by renal denervation (RDN) in a real-world setting. Methods: The Global SYMPLICITY Registry (NCT01534299) is a prospective, open-label, multicenter registry conducted worldwide to evaluate the safety and effectiveness of RDN in patients with uncontrolled hypertension. Office and 24-h ambulatory BP were reported for all patients, based on the presence of OSA. Results: Among 1868 patients, self-reported OSA occurred in 205 patients, who were more likely to be men (76 vs 57%, P < 0.001), have a higher BMI (34 ± 6 vs 30 ± 5 kg/m2, P < 0.001), chronic kidney disease (30 vs 21%, P = 0.003), left ventricular hypertrophy (25 vs 15%, P < 0.001), and type 2 diabetes (50 vs 36%, P < 0.001). Among OSA patients, the baseline office SBP (166 ± 26 mmHg) was reduced by 14.0 ± 25.3 mmHg at 6 months (P < 0.001). Ambulatory 24-h SBP was reduced by 4.9 ± 18.0 mmHg (n = 115, P = 0.005) from 155 ± 19 mmHg at baseline. The 6-month change in SBP from baseline was not statistically different between OSA and non-OSA patients. BP reduction after RDN was also similar in OSA patients already treated with and not treated with continuous positive airway pressure. Conclusion: RDN resulted in significant BP reductions at 6 months in hypertensive patients with and without OSA, and regardless of continuous positive airway pressure usage in OSA patients.