Radiofrequency renal denervation (RF RDN) is a novel therapy for uncontrolled hypertension. In the recent sham-controlled SPYRAL HTN-ON MED study, office-based systolic blood pressure (oSBP) and nighttime BP were reduced significantly. This study examined the cost-effectiveness of RF RDN in the context of the Japanese healthcare system based on this latest clinical evidence. Clinical events, costs, and quality-adjusted life-years (QALYs) were projected using a decision-analytic Markov model adjusted to Japanese incidence data. Risk reduction in clinical events from changes in oSBP was calculated based on a published meta-regression of 47 trials of intentional hypertension treatment. Demographics and results from the SPYRAL HTN-ON MED trial (oSBP effect size -4.9mmHg vs. sham) were utilized in the base case analysis. Additional scenarios were explored including the potential added benefit of improved night-time control. Costs were sourced from claims data and published literature. The incremental cost-effectiveness ratio (ICER) was evaluated against a cost-effectiveness threshold of ¥5000000 per QALY gained. RF RDN was projected to reduce clinical events (10-year relative risks: 0.80 for stroke, 0.88 for myocardial infarction, and 0.75 for heart failure). Over lifetime, RF RDN added 0.36 QALYs at the incremental cost of ¥923723, resulting in an ICER of ¥2565236 per QALY gained. Under the assumption of added night-time benefit, the ICER decreased to ¥2155895 per QALY. Cost-effectiveness findings were robust across all tested scenarios. The findings of this model-based analysis suggest that RF RDN can provide meaningful clinical event reductions and is a cost-effective treatment option in the Japanese healthcare system.