Many antiseizure medications (ASMs) affect ion channel function. We investigated whether ASMs alter the risk of cardiac events in patients with corrected QT (QTc) prolongation. The study included people from the Rochester-based Long QT syndrome (LQTS) Registry with baseline QTc prolongation and history of ASM therapy (n = 296). Using multivariate Anderson-Gill models, we assessed the risk of recurrent cardiac events associated with ASM therapy. We stratified by LQTS genotype and predominant mechanism of ASM action (Na+ channel blocker and gamma-aminobutyric acid modifier.) There was an increased risk of cardiac events when participants with QTc prolongation were taking vs off ASMs (HR 1.65, 95% confidence interval [CI] 1.36–2.00, P < 0.001). There was an increased risk of cardiac events when LQTS2 (HR 1.49, 95% CI 1.03–2.15, P = 0.036) but not LQTS1 participants were taking ASMs (interaction, P = 0.016). Na+ channel blocker ASMs were associated with an increased risk of cardiac events in participants with QTc prolongation, specifically LQTS2, but decreased risk in LQTS1. The increased risk when taking all ASMs and Na+ channel blocker ASMs was attenuated by concurrent beta-adrenergic blocker therapy (interaction, P < 0.001). Gamma-aminobutyric acid modifier ASMs were associated with an increased risk of events in patients not concurrently treated with beta-adrenergic blockers. Female participants were at an increased risk of cardiac events while taking all ASMs and each class of ASMs. Despite no change in overall QTc duration, pharmacogenomic analyses set the stage for future prospective clinical and mechanistic studies to validate that ASMs with predominantly Na+ channel blocking actions are deleterious in LQTS2, but protective in LQTS1.