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Background Patients with drug-refractory non-obstructive hypertrophic cardiomyopathy (NOHCM) lack effective invasive treatment options. This study aimed to evaluate the safety and effectiveness of percutaneous intramyocardial septal radiofrequency ablation (PIMSRA, Liwen procedure) in patients with NOHCM and severe septal hypertrophy (≥28 mm).Method This single-arm, open-label, prospective study enrolled 20 adult patients with drug-refractory NOHCM between June 2017 and June 2023. Patients underwent PIMSRA and were followed for a median of 15 months. Outcomes included changes in septal thickness, quality of life (Kansas City Cardiomyopathy Questionnaire-12, KCCQ-12) and myocardial function.Results No major adverse clinical events occurred within 30 days after the procedure. The maximum interventricular septal thickness decreased significantly from 31.3 mm to 17.4 mm (mean difference: −13.9 mm; 95% CI −15.92 to −11.88). Left atrial volume index and left ventricular mass index also decreased significantly. Improvements in global longitudinal strain and global radial strain were observed, indicating possibly enhanced myocardial performance. KCCQ-12 scores improved from 65.6 to 84.4 (mean difference: 18.78; 95% CI 11.62 to 25.93). Patients after PIMSRA were not found to have an increased risk of arrhythmias such as atrial fibrillation, high-grade conduction block or non-sustained ventricular tachycardia during the follow-up.Conclusions PIMSRA was associated with a reduction of myocardial septal thickness and improvement in functional status in patients with NOHCM. The absence of major adverse events is also encouraging, but larger studies with a control arm are needed to confirm long-term safety.Trial registration number ChiCTR1900020530.