Background: Patients with Brugada syndrome (BrS) are known to have arrhythmic events after alcohol drinking and are recommended to avoid its excessive intake. Mechanisms underlying the alcohol-induced cardiac events are however unknown. This study aimed to test the hypothesis whether activity of alcohol-metabolizing enzymes determines fatal arrhythmic events after drinking alcohol. Methods: A total of 198 Japanese patients with BrS were enrolled in this study. These patients were classified into symptomatic (n = 90) and asymptomatic (n = 108) groups. The former was divided into an alcohol-related group (syncope after alcohol drinking, n = 16) and an alcohol-unrelated group (n = 74). Polymerase chain reaction was performed to determine genetic variants of genes encoding alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2). Results: The genotype distribution for ALDH2 was not significantly different between symptomatic and asymptomatic groups and between alcohol-related and alcohol-unrelated groups. The genotype distribution for ADH1B was not significantly different between symptomatic and asymptomatic groups, but the genotype ADH1B His/His was significantly more prevalent in the alcohol-related group than in the alcohol-unrelated group (81.3% vs 50%, P = .023). In multivariate logistic regression analysis, the genotype of ADH1B His/His was independently associated with syncope after alcohol drinking (odds ratio, 5.746; 95% confidence interval, 1.580-28.421; P = .007). Conclusions: Arrhythmic events after alcohol drinking was associated with enhanced activity of alcohol-metabolizing enzyme ADH1B in our cohort of BrS. Therefore, the lifestyle change to avoid the excessive alcohol intake deserves attention.