It has been reported that bepridil prevents ventricular fibrillation (VF) in patients with Brugada syndrome, but the comparative efficacy with and without mutation in the SCN5A gene has not been elucidated. The purpose of this study was to assess the efficacy of low-dose bepridil (100 mg/day) for VF prevention in patients with Brugada syndrome with and without SCN5A mutation. Among 130 patients with Brugada-type electrocardiogram (ECG), low-dose bepridil was administered to seven patients because of repetitive VF episodes, including three with and four without SCN5A mutation. Preventive effect for VF recurrence and changes of the ECG and the signal-averaged ECG were evaluated. Frequencies of VF episodes were reduced after treatment with low-dose bepridil in all three patients with the SCN5A mutation (before: 0.33 versus after: 0.02 episodes/month, P < 0.01), but not in all four patients without the SCN5A mutation (before: 0.43 versus after: 2.94 episodes/month, P = nonsignificant). Levels of ST-segment elevation at J points and duration of low-amplitude signals less than 40 µV in the terminal filtered QRS complex (LAS40) in signal-averaged ECG were improved exclusively in patients with the SCN5A mutation. Treatment with bepridil prevented recurrence of VF along with improvement of ST elevation and LAS40 in patients with Brugada syndrome with the SCN5A mutation.