Primary prevention patients with ischaemic cardiomyopathy and chronic total occlusion of an infarct-related coronary artery (CTO) are at a particularly high risk of implantable cardioverter-defibrillator (ICD) therapy occurrence. The trial was designed to evaluate the efficacy of preventive CTO-related substrate ablation strategy in ischaemic cardiomyopathy patients undergoing primary prevention ICD implantation. The PREVENTIVE VT study was a prospective, multicentre, randomized trial including ischaemic patients with ejection fraction ≤40%, no documented ventricular arrhythmias (VAs), and evidence of scar related to the coronary CTO. Patients were randomly assigned 1:1 to a preventive substrate ablation before ICD implantation or standard therapy with ICD implantation only. The primary outcome was a composite of appropriate ICD therapy or unplanned hospitalization for VAs. Secondary outcomes included the primary outcome’s components, the incidence of appropriate ICD therapies, cardiac hospitalization, electrical storm, and cardiovascular (CV) mortality. Sixty patients were included in the study. During the mean follow-up of 44.7 ± 20.7 months, the primary outcome occurred in 5 (16.7%) patients undergoing preventive substrate ablation and in 13 (43.3%) patients receiving only ICD [hazard ratio (HR): 0.33; 95% confidence interval (CI): 0.12–0.94; P = 0.037]. Patients in the preventive ablation group also had fewer appropriate ICD therapies (P = 0.039) and the electrical storms (Log-rank: P = 0.01). While preventive ablation also reduced cardiac hospitalizations (P = 0.006), it had no significant impact on CV mortality (P = 0.151). Preventive ablation of the coronary CTO-related substrate in patients undergoing primary ICD implantation is associated with the reduced risk of appropriate ICD therapy or unplanned hospitalization due to VAs. Preventive ablation of coronary total occlusion-related substrate at the time of primary prevention defibrillator implantation is associated with a reduced risk of appropriate defibrillator therapy or unplanned hospitalization due to ventricular arrhythmias.