BackgroundThe majority of sudden cardiac death (SCD) in patients with heart failure occurs in those with mild‐moderate left ventricular (LV) systolic dysfunction (LVEF 36–50%) who under current guidelines are ineligible for primary prevention implantable cardiac defibrillator (ICD) therapy. Recent data suggest that cardiac magnetic resonance (CMR) evidence of replacement fibrosis forms a substrate for malignant arrhythmia and therefore potentially identifies a subgroup at increased risk of SCD. Our hypothesis is that among patients with mild‐moderate LV systolic dysfunction, a CMR‐guided management strategy for ICD insertion based on the presence of scar or fibrosis is superior to a current strategy of standard care.Methods/DesignCMR GUIDE is a prospective, multicenter randomized control trial enrolling patients with mild‐moderate LV systolic dysfunction and CMR evidence of fibrosis on optimal heart failure therapy. Participants will be randomized to receive either a primary prevention ICD or an implantable loop recorder (ILR). The primary endpoint is the time to SCD or hemodynamically significant ventricular arrhythmia (VF or VT) during an average 4‐year follow‐up. Secondary endpoints include quality of life assessed by Minnesota Living with Heart Failure Questionnaire, heart failure related hospitalizations, and a cost‐utility analysis. Clinical trials.gov identifier NCT01918215.DiscussionCMR GUIDE trial will add substantially to our understanding of the role of myocardial fibrosis and the risk of developing life‐threatening ventricular arrhythmias. If the superiority of a CMR‐guided approach over standard care is proven, it may change international clinical guidelines, with the potential to considerably increase survival in this growing patient population.