Sex is a major determinant of the incidence and clinical presentation in arrhythmia syndromes such as Brugada syndrome (BrS). We generated a novel SCN5A-G1408R/+ knock-in mouse model mimicking key features of human BrS regarding male predominance and susceptibility to ventricular tachycardias. This study aimed to explore the effect and molecular mechanisms of androgen deprivation on cardiac arrhythmogenicity in a mouse model of BrS. Animals were studied using surface ECG with and without flecainide challenge (10 mg/kg body weight), telemetric recordings, molecular, biochemical as well as histological analyses. To study the effect of antiandrogenic treatments on the rhythmogenic state and its influence on transcriptional alterations of cardiac ion channel genes, male G1408R/+ mice were either chronically treated with the androgen receptor (AR) blocker flutamide by subcutaneously implanted osmotic pumps or orchiectomized. Sex-dependent analysis showed that 81% (25/31 animals) of male G1408R/+ and only 14% (2/14 animals) of their female littermates developed flecainide-induced polymorphic ventricular tachycardias (VT). Only male G1408R/+ mice, previously 100% inducible for VT underwent androgen deprivation (flutamide for 4 weeks vs. orchiectomy). The arrhythmogenic phenotype was rescued in both groups of antiandrogenic therapy. VT incidence in the flutamide group was reduced to 13% (2/16), while VT in the orchiectomy group declined to 33% (3/9). At baseline, (untreated) male G1408R/+ mice exhibited reduced cardiac expression of NaV1.5 protein compared to male wild type (wt) mice, particularly in the right ventricular myocardium. Treatment with flutamide for 4 weeks resulted in increased NaV1.5 expression in male G1408R/+ mice to levels similar to male wt mice. Interestingly, orchiectomized G1408R/+ mice revealed levels of NaV1.5 protein even higher compared to wt mice, which were particularly abundant in the right ventricular free wall. We observed a significant anti-arrhythmic effect induced by androgen deprivation in the G1408R/+ mouse model mimicking human BrS. Our data indicate that the anti-arrhythmic effect is potentially driven by increasing right ventricular NaV1.5 membrane expression as a result of anti-androgenic treatment.