Background In randomized controlled trials, perioperative administration of amiodarone has been shown to reduce the incidence of postoperative atrial arrhythmias and length of stay (LOS) among patients undergoing coronary bypass surgery. However, little is known about the use or effectiveness of perioperative amiodarone in routine clinical practice. Methods and Results We studied patients ≥18 years old without a previous history of atrial or ventricular arrhythmias who underwent elective coronary bypass surgery between 2013 and 2014 within a network of 235 US hospitals. Perioperative amiodarone was defined as receipt of amiodarone either on the day of or the day preceding surgery. We used covariate-adjusted modeling and instrumental variable methods to examine the association between receipt of amiodarone and the development of atrial arrhythmias, in-hospital mortality, readmission, LOS, and cost. Of 12 758 patients, 2195 (17.2%) received perioperative amiodarone, 3330 (26.1%) developed atrial arrhythmias postoperatively, and the average LOS was 6.4 days (±2.6 days). Instrumental variable analysis showed that receipt of perioperative amiodarone was associated with lower risk of atrial arrhythmias (risk difference -11 percentage points, 95% CI -19 to -4 percentage points; P=0.002) and a shorter LOS (-0.7 day, 95% CI -1.39 to -0.01 days; P=0.048). There was no association between receipt of perioperative amiodarone and in-hospital mortality, cost, or readmission. Conclusions Among patients undergoing coronary bypass surgery without previous arrhythmias, perioperative amiodarone is associated with a lower risk of atrial arrhythmias and shorter LOS. These findings are consistent with previous randomized trials and lend support to current guideline recommendations.