Aims Ventricular tachyarrhythmias (VT/VF) are common among patients with prior myocardial infarction (MI). MANTRA-VT trial was designed to compare the efficacy and safety of early substrate-based radiofrequency catheter ablation (RFCA) to antiarrhythmic drug (AAD) therapy for ventricular tachyarrhythmias.Methods and results We randomly assigned 58 AAD na & iuml;ve post MI patients with implantable cardioverter defibrillator (ICD) and at least one documented VT/VF episode after the device implantation to an initial treatment strategy of substrate-based RFCA or AAD therapy. The primary endpoint was cumulative number of ventricular tachyarrhythmias (VT/VF burden) at 12 months. The secondary endpoints included all-cause mortality, hospitalization, adverse events, and VT/VF burden at 24 months. Analyses were performed on an intention-to-treat basis. The median number of VT/VF episodes at 12 months was zero in both the RFCA (range 0-3) and the AAD group (range 0-23) (P = 0.454), whereas the rate of appropriate ICD shocks was 7% and 30% in the RFCA and the AAD groups (P = 0.026), respectively. During the extended follow-up, 82% of the patients in the RFCA group and 63% in the AAD group had no ICD therapies (P = 0.012). There was no significant difference between the groups in total mortality (HR 1.02, 95% CI 0.20-5.11, P = 0.86) and hospitalization (HR 1.35, 95% CI 0.36-5.09. P = 0.66) at 24 months. Therapy-related adverse events occurred in 3.6% and 16.7% of the patients in the RFCA and the AAD groups (P = 0.10), respectively.Conclusion Early substrate-based RFCA was associated with reduced risk of ICD therapies, but with no meaningful difference in VT/VF burden, mortality, hospitalization, and adverse events.