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Abstract Aims Amiodarone reduces the incidence of atrial fibrillation (AF) following coronary artery bypass surgery; however, the benefit of perioperative amiodarone in patients undergoing septal myectomy (SM) for obstructive hypertrophic cardiomyopathy (oHCM) has not been studied. We hypothesized that prophylactic amiodarone would reduce the incidence of postoperative AF (POAF) following SM for oHCM. Methods and Results A single‐centre, pre‐post intervention open‐label study of oral amiodarone (200 mg twice daily starting 7 days preoperatively and 200 mg once daily continuing for 30 days postoperatively) in patients without prior AF undergoing SM for oHCM from 2014 to 2018. The primary outcome was incident AF within 30 days. Secondary outcomes were unplanned readmission, AF treatment, total and intensive care unit (ICU) length of stay (LOS), and pacemaker implantation for high‐grade atrioventricular (AV) block. 61 patients met inclusion criteria with 34 (55.8%) in the pre‐intervention (control) group and 27 (44.2%) in the post‐intervention (amiodarone) group. The incidence of POAF was 11.0% in the amiodarone group compared with 38.2% in the control group (P = 0.017). After adjusting for age, amiodarone was associated with less POAF [adjusted odds ratio (aOR) 0.21; 95% confidence interval (CI) 0.05, 0.76; P = 0.016]. ICU (2 days [IQR 1, 4] vs. 3 days [IQR 2, 4]; P = 0.165) and total (6 days [IQR 5, 6] vs. 6 days [IQR 5, 7]; P = 0.165) LOS were similar, as was the rate of pacemaker implantation (7.4% vs. 8.3%, P > 0.999). There were no adverse events associated with amiodarone. Conclusions Perioperative oral amiodarone is safe and was associated with lower incidence of POAF following SM for oHCM.