Background: Identification of patients with non-ischemic cardiomyopathy who benefit from prophylactic implantation of a cardioverter-defibrillator (ICD) remains an unmet clinical need. We hypothesized that periodic repolarization dynamics (PRD), a marker of repolarization instability associated with sympathetic activity, could be used to identify patients that benefit from prophylactic ICD-implantation. Methods: Heart-failure (DANISH) study, in which patients with non-ischemic cardiomyopathy, left-ventricular ejection fraction (LVEF) ≤35% and elevated N-terminal pro-brain natriuretic peptides (NT-proBNP) were randomized to ICD-implantation or control group. Patients were included in the PRD-substudy if they had a 24-hour Holter monitor recording at baseline with technically acceptable ECG signals during the night hours (00:00-06.00 AM). PRD was assessed using wavelet analysis according to previously validated methods. Primary endpoint was all-cause mortality. Cox-regression models were adjusted for age, sex, NT-proBNP, estimated glomerular filtration rate, LVEF, atrial fibrillation, ventricular pacing, diabetes mellitus, cardiac resynchronization therapy and mean heart rate. We proposed PRD ≥10deg2 as exploratory cut-off value for ICD-implantation. Results: Seven-hundred and forty-eight of the 1,116 DANISH patients qualified for the PRD-substudy. During a mean follow-up period of 5.1±2.0 years, 82 of 385 patients died in the ICD group and 85 of 363 patients died in the control group (p-value=0.40). In Cox-regression analysis, PRD was independently associated with mortality (HR 1.28 [1.09-1.50] per SD increase; p-value = 0.003). Moreover, PRD was significantly associated with mortality in the control group (HR 1.51 [1.25-1.81]; p<0.001) but not in the ICD-group 1.04 [0.83-1.54]; p-value=0.71). There was a significant interaction between PRD and the effect of ICD-implantation on mortality (p-value 0.008), with patients with higher PRD having the greater benefit in terms of mortality reduction. ICD-implantation was associated with an absolute mortality reduction of 17.5% in the 280 patients with PRD ≥10deg2 (HR 0.54 [0.34-0.84]; p-value=0.006; number needed to treat 6), but not in the 468 patients with PRD<10deg2 (HR 1.17 [0.77-1.78]; p-value=0.46; p-value for interaction 0.01). Conclusions: Increased PRD identified patients with non-ischemic cardiomyopathy, where prophylactic ICD-implantation led to significant mortality reduction.