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Left ventricular septal (LVS) pacing reduces ventricular dyssynchrony and improves cardiac function relative to right ventricular apex (RVA) pacing in animals. We aimed to establish permanent placement of an LVS pacing lead in patients using a transvenous approach through the interventricular septum.Ten patients with sinus node dysfunction scheduled for dual-chamber pacemaker implantation were prospectively enrolled. A custom pacing lead with extended helix was introduced via the left subclavian vein and, after positioning against the right ventricular septum (RVS) using a preshaped guiding catheter, driven through the interventricular septum to the LVS. The acute hemodynamic effect of RVA, RVS, and LVS pacing was evaluated by invasive LVdP/dtmax measurements. The lead was successfully delivered to the LVS in all patients. Procedure time and fluoroscopy time shortened with experience. QRS duration was shorter during LVS pacing (144±20 ms) than during RVA (172±33 ms; P=0.02 versus LVS) and RVS pacing (165±17 ms; P=0.004 versus LVS). RVA and RVS pacing reduced LVdP/dtmax compared with baseline atrial pacing (−7.1±4.1% and −6.9±4.3%, respectively), whereas LVS pacing maintained LVdP/dtmax at baseline level (1.0±4.3%; P=0.001 versus RVA and RVS). R-wave amplitude and pacing threshold were 12.2±6.7 mV and 0.5±0.2 V at implant and remained stable during 6-month follow-up without lead-related complications.Permanent placement of an LVS pacing lead by transvenous approach through the interventricular septum is feasible in patients. LVS pacing preserves acute left ventricular pump function. This new pacing method could serve as an alternative and hemodynamically preferable approach for antibradycardia pacing.