Abstract Background Septal reduction techniques play a pivotal role in mitigating morbidity and mortality among patients with obstructive hypertrophic cardiomyopathy (oHCM). While trans-apical intramyocardial septal radiofrequency ablation (PIMSRA or LIWEN procedure) has shown promise in reducing left ventricular outflow tract (LVOT) gradients and improving symptoms in oHCM patients, it is associated with complications such as cardiac tamponade and atrioventricular block. Objective This study introduces a novel approach for transcatheter radiofrequency ablation of hypertrophic septum via femoral access, utilizing the DragonFire Transcatheter Myocardial Puncture and Radiofrequency Ablation System. We aim to evaluate its safety and medium-term outcomes in patients with oHCM. Methods A prospective, single-center, single-arm study of tf-PIMSRA was conducted in patients with drug-refractory oHCM. Ten patients were enrolled and underwent the procedure under the guidance of transesophageal echocardiography. The primary outcome was 30-day major adverse clinical events, with secondary outcomes including 90-day improvements in outflow obstruction and quality of life. Results All patients, with an average age of 57±10 years, including 4 males, underwent the procedure successfully without any complications, including major adverse clinical events or conduction abnormalities. The average duration of the procedure was 125.2±34.6 minutes, with an average ablation time of 38.69±18.29 minutes and ablation energy of 3.60±1.49KJ. At 90-day follow-up, significant reductions were observed in peak LVOT gradients (resting gradient: from 82.00 [56.00] mmHg to 14.00 [6.25] mmHg; p < 0.001; provoked gradient: from 102.00 [76.25] mmHg to 33.00 [16.50] mmHg; p = 0.002), and interventricular septum thickness (from 22.00 [19.00] mm to 17.00 [15.00] mm; p = 0.002). These improvements were associated with enhancements in NYHA functional classification (from 3.00 [2.75] to 1.00 [1.00]; p < 0.0001), Kansas City Cardiomyopathy Questionnaire scores (from 59.00 [44.50] to 80.00 [77.25]; p < 0.02), 6-minute walk distance (from 441 [400] m to 480 [465] m; p < 0.01), and pro B-type natriuretic peptide levels (from 1738.00 [1113.25] pg/ml to 252.00 [200.00] pg/ml; p = 0.002). All patients achieved New York Heart Association functional class I or II at follow-up. Conclusions Transfemoral PIMSRA appears to be a safe and effective procedure for relieving LVOT obstruction and symptoms in patients with drug-refractory oHCM. These findings support further investigation through randomized clinical trials comparing it with established septal reduction therapies.Patient-Level Outcomes for the trans-fem