Aims Catheter-based renal artery denervation (RDN) has been shown to lower blood pressure (BP) in certain patients with uncontrolled hypertension. Isolated systolic hypertension (ISH) (systolic BP [SBP] ≥140 mmHg and diastolic BP <90 mmHg), characterized by increased vascular stiffness, is the predominant hypertensive phenotype in elderly patients. This study compared baseline characteristics and SBP change at 6 months between patients with ISH and combined systolic–diastolic hypertension (CH). Methods and results This study pooled data from 1103 patients from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. A total of 429 patients had ISH, and 674 had CH. Patients with ISH were significantly older than those with CH (66 vs. 55 years), had more type 2 diabetes mellitus (52.9 vs. 34.6%), and a lower estimated glomerular filtration rate (71.8 vs. 78.6 mL/min/1.73 m2); all P < 0.001. At 6 months, the SBP drop for CH patients was −18.7 ± 23.7 mmHg compared with a reduction of −10.9 ± 21.7 mmHg for ISH patients −7.8 mmHg, 95% confidence interval, CI, −10.5, −5.1, P < 0.001). The change in 24-h SBP at 6 months was −8.8 ± 16.2 mmHg in patients with CH vs. −5.8 ± 15.4 mmHg in ISH (−3.0 mmHg, 95% CI −5.4, −0.6, P = 0.015). Presence of ISH at baseline but not age was associated with less pronounced BP changes following the procedure. The strongest predictor of office SBP reduction at 6 months was CH, followed by aldosterone antagonist use and non-use of vasodilators. Conclusion The reduction in BP among patients with ISH following RDN was less pronounced than the reduction in patients with CH. Clinical.Trials.gov identifiers NCT01534299 and NCT01418261.