In heart failure and atrial fibrillation, a persistent Na+current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV1.8 contributes to arrhythmogenesis by inducing a INaL. Genome-wide association studies indicate that mutations in theSCN10Agene (NaV1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrialSCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the INaLand action potential duration. Ca2+measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca2+leak. The INaLwas significantly reduced in atrialSCN10AKO CMs as well as after specific pharmacological inhibition of NaV1.8. No effects on atrial APD90were detected in any groups. BothSCN10AKO and specific blockers of NaV1.8 led to decreased Ca2+spark frequency and a significant reduction of arrhythmogenic Ca2+waves. Our experiments demonstrate that NaV1.8 contributes to INaLformation in human atrial CMs and that NaV1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore NaV1.8 could be a new target for antiarrhythmic strategies.