AbstractAbnormal QRS duration and amplitudes on the electrocardiogram are indicative of cardiac pathology and are associated with adverse outcomes. The causal nature of these associations remains uncertain and could be due to QRS abnormalities being a symptom of cardiac damage rather than a factor on the causal pathway. By performing Mendelian randomization (MR) analyses using summary statistics of genome wide association study consortia with sample sizes between 20,687 and 339,224 individuals, we aimed to determine which cardiovascular risk factors causally lead to changes in QRS duration and amplitude (Sokolow-Lyon, Cornell and 12-leadsum products). Additionally, we aimed to determine whether QRS traits have a causal relationship with mortality and longevity. We performed inverse-variance weighted MR as main analyses and MR-Egger regression and weighted median estimation as sensitivity analyses. We found evidence for a causal relationship between higher blood pressure and larger QRS amplitudes (systolic blood pressure on Cornell: 55SNPs, causal effect estimate per 1 mmHg = 9.77 millimeters·milliseconds (SE = 1.38,P = 1.20 × 10⁻¹²) and diastolic blood pressure on Cornell: 57SNPs, causal effect estimate per 1 mmHg = 14.89 millimeters·milliseconds (SE = 1.82,P = 3.08 × 10⁻¹⁶), but not QRS duration. Genetically predicted QRS traits were not associated with longevity, suggesting a more prominent role of acquired factors in explaining the well-known link between QRS abnormalities and outcome.