In heart failure, increased CaMKII activity is decisively involved in arrhythmia formation. Here, the authors introduce the neuronal sodium channel Na(V)1.8 as a CaMKII downstream target as its specific knock-out reduces arrhythmias and improves survival in a CaMKII-overexpressing mouse model. An interplay between Ca2+/calmodulin-dependent protein kinase II delta c (CaMKII delta c) and late Na+ current (I-NaL) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na(V)1.8 for CaMKII delta c-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na(V)1.8, we demonstrate that Na(V)1.8 contributes to I-NaL formation. In addition, we reveal a direct interaction between Na(V)1.8 and CaMKII delta c in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na(V)1.8 and CaMKII delta c, we show that Na(V)1.8-driven I-NaL is CaMKII delta c-dependent and that Na(V)1.8-inhibtion reduces diastolic SR-Ca2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKII delta c-overexpressing HF mice is reduced when a Na(V)1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKII delta c downstream target which may constitute a prognostic and antiarrhythmic strategy.