Screening tests conducted at rest may be inadequate for the prediction of the T-wave oversensing (TWOS) in subcutaneous implantable cardioverter defibrillator (S-ICD) candidates with Brugada syndrome (BrS) because of the dynamic nature of electrocardiogram (ECG) morphology. We evaluated the utility of ECG screening during drug challenge (DC) for prediction of TWOS in BrS patients implanted with an S-ICD. The study enrolled 6 consecutive BrS patients implanted with an S-ICD. In addition to baseline ECG screening, pre-implant screening during DC using a sodium channel blocker was performed in all patients. All patients underwent appropriate morphological analysis on baseline ECG screening; however, 2 BrS patients (33%) showed inappropriate sensing during DC. During 243 days of follow-up after S-ICD implantation, no patient experienced an appropriate shock. TWOS was confirmed during exercise testing in one of 2 patients who showed inappropriate sensing during DC. However, one patient with appropriate sensing during DC experienced recurrent episodes of inappropriate shocks due to TWOS during exercise. The present initial experience indicates that further studies are needed to detect the risk for TWOS from an S-ICD in BrS patients.