Antimicrobial incise drapes adhere to a patient's skin during surgery in an attempt to reduce surgical infections. We describe a patient undergoing repeated aortic valve replacement who experienced sudden ventricular fibrillation before median sternotomy. External defibrillation was unsuccessful on multiple attempts using several defibrillators. On removal of the incise drape from the patient's chest, external defibrillation was immediately successful. Increased transthoracic impedance can be caused by multiple factors and may prevent defibrillation. To our knowledge, this is the first reported case of an antimicrobial incise drape preventing defibrillation. If external defibrillation, cardioversion, or pacing is indicated intraoperatively, we recommend prompt removal of the antimicrobial incise drapes before electrode placement if the drapes overlay the intended pad position. Since this case, our institutional practice has now changed to placement of 2 external adhesive defibrillator electrodes onto the patient's skin lateral to the surgical field before incise drape application to allow for defibrillation.