Abstract Background Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and in particular the effects of gene variants on clinical outcomes remain poorly understood. Purpose To investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients. Methods We analyzed 487 DCM patients by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality, heart transplantation or left ventricular assist device (D/HTx/VAD); 2) sudden cardiac death or malignant ventricular arrhythmias (SCD/MVAs); 3) heart failure related death, heart transplantation or left ventricular assist device implantation (DHF/HTx/VAD). Results A total of 187 pathogenic/likely pathogenic variants were found in 180 patients (37%): 55 (11%) TTN; 19 (4%) LMNA; 24 (5%) structural cytoskeleton-Z disk genes; 16 (3%) desmosomal genes; 47 (10%) sarcomeric genes; 8 (2%) ion channels genes; 11 (2%) other genes. The occurrence of D/HTx/VAD was no different between variant carriers and non-carriers (p=0.17). However, carriers of desmosomal and LMNA variants experienced the highest rate of SCD/MVA, which was independent of the left ventricular ejection fraction. Conclusions Desmosomal and LMNA gene variants identify the subset of DCM patients at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless the left ventricular ejection fraction. Acknowledgement/Funding National Institutes of Health grants R01 HL69071, HL116906, and AHA17GRNT33670495