Aims: This study aimed to compare left ventricular (LV) function and clinical/biologic features between septal and apical pacing over a six-month follow-up period in patients with high-grade atrioventricular block. Methods: This non-randomized prospective single-center study includes patients allocated to receive an apical or midseptal ventricular lead. Computed tomography was used to confirm the intended lead tip position. Pacemaker parameters, QRS duration, LV volumes and ejection fraction, European Quality of Life Score, Functional Class, Six-minute walk test, and NT-proBNP‎ were assessed at baseline and six months later. Results: A pacemaker was implanted in 58 patients (27 in the midseptal group and 31 in the apical group). No significant differences between the two groups were observed at baseline. Paced QRS duration was significantly lower in the midseptal than apical pacing group (‎P=0.002‎)‎. After six months follow-up period, pacing parameters remained comparable between the two groups while patients assigned to the midseptal pacing group have a higher ejection fraction (‎P=‎0.016‎). Higher LV end-diastolic and end-systolic volumes ‎were observed in the apical than midseptal pacing group at 6 months (‎P=0.008&‎P=0.003, respectively‎). At 6 months, the midseptal group has lower serum NT-proBNP (‎P=0.003) and higher six-minute walk test distance (P‎=0.030). Nevertheless, EuroQol index and NYHA>1 show no statistical difference. Conclusions: Compared ‎with right ventricular (RV) apical pacing, midseptal pacing was associated with better LV ejection fraction and six-minute ‎walk test, and lower LV volumes and NT-proBNP levels. RV midseptal pacing might be a ‎better option than regular RV apical pacing to lessen its negative effects.‎