Alcohol septal ablation is an established treatment for selected patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction (LVOT). The safety and efficacy of septal microsphere embolization (SME) have not been studied. We conducted a retrospective analysis of SME procedures performed at our center from 2006 to 2021 using 75-µm microspheres. The primary end point was LVOT gradient reduction. Secondary outcomes included periprocedural mortality, conduction disturbances, access site complications, and duration of hospitalization. The population comprised 76 patients (median age 61 years, men 43%). Dyspnea New York Heart Association ≥III was present in 65 patients (86%); ventricular tachycardia and previous syncope were described in 4% and 18%, respectively. Median duration of hospitalization was 13 days, and the time to first follow-up was 4 months. SME resulted in a significant reduction at rest (41 vs 12 mm Hg, mean Δ PG = −71%, p <0.001) and provoked LVOT gradients (94 vs 29 mm Hg, mean Δ PG = −75%, p <0.001). Periprocedural death occurred in 1 patient (1%) who underwent SME after transcatheter aortic valve replacement. Complete atrioventricular block was observed in 5 patients (7%). Left bundle branch block was diagnosed in 1 case (1%) and right bundle branch block in 3 (4%). Access site complications were observed in 4 patients (5%). In conclusion, SME is a safe and effective alternative to alcohol septal ablation. The potential advantages of microspheres are still to be investigated in prospective studies.