Objectives The purpose of this study was to examine the role of mexiletine, a late sodium current (INa-L) blocker, in acute termination of torsades de pointes (TdP) refractory to conventional therapy in acquired long QT syndromes (LQTS). Background Long QT interval can predispose to TdP and is therefore associated with significant mortality. Currently, there is no available pharmacotherapy to target directly the ionic basis of most LQTS for the acute termination of TdP. Earlier evidence highlighted the role of INa-L in the pathophysiology of long QT and TdP, particularly in patients with congenital LQTS. Methods Twelve patients with TdP caused by acquired LQTS were treated with mexiletine after failure of conventional treatment including discontinuation of QT-prolonging drugs, intravenous administration of magnesium, and correction of serum electrolyte abnormalities. Results No recurrence of TdP occurred within 2 h after initiation of treatment with mexiletine in all 12 patients. Macro T-wave alternans accompanied by QT prolongation, an electrocardiographic precursor of TdP that was seen in 3 patients, was also abolished by mexiletine. Treatment with mexiletine shortened the QTc interval from 599 ± 27 ms to 514 ± 16 ms (p = 0.001). The interval from the peak to the end of the T-wave (Tp-e interval) decreased from 145 ± 18 ms to 106 ± 9 ms (p = 0.005). The Tp-e/QT ratio decreased from 0.27 ± 0.02 to 0.23 ± 0.018 (p = 0.01). Mexiletine had no significant effect on QRS complex duration. Conclusions INa-L blockade with mexiletine may be an effective treatment approach to terminate refractory TdP from several acquired causes of LQTS. © 2015 American College of Cardiology Foundation PUBLISHED BY ELSEVIER INC.