RPR260243 increased the delayed rectifier current in guinea pig myocytes but, when administered alone, had little effect on action potential parameters in these cells. RPR260243 fully reversed the action potential-prolonging effects of dofetilide in this preparation. HERG activator RPR260243 displayed no activator-like effects on other voltage-dependent ion channels, including the closely related erg3 K+ channel. Using the Langendorff heart method, we found that 5 μM RPR260243 increased T-wave amplitude, prolonged the PR interval, and shortened the QT interval. We believe RPR260243 represents the first known HERG channel activator and that the drug works primarily by inhibiting channel closure, leading to a persistent HERG channel current upon repolarization.