Programmed electrical stimulation (PES) and 24-hour Holter monitoring were compared in 30 patients with ventricular tachycardia (VT) or ventricular fibrillation (VF) before and during treatment with mexiletine. Before treatment, all patients had ≥30 ventricular premature complexes (VPCs)/hr and 22 patients had nonsustained VT on Holter. All had inducible sustained VT by PES (one to three extrastimuli). Mexiletine was effective in only 23% by PES criteria (VT no longer inducible or ≤15 beats in duration and effective in 57%, 57%, and 73% by Holter criteria I, II, and III, respectively (Holter I ≥50% reduction of VPCs, ≥90% reduction of couplets and abolition of nonsustained VT; Holter II ≥83% reduction of VPCs and abolition of VT; Holter III abolition of VT in patients who had VT during baseline Holter). Results of PES and Holter were discordant in 67%, 60%, and 55% (PES vs Holter I, II, and III, respectively). The majority (≥75%) of the discordance occurred due to mexiletine appearing effective by Holter criteria but ineffective by PES criteria (suggesting insensitivity of efficacy by Holter criteria and/or nonspecificity of induced VT during treatment with mexiletine). Conclusions: (1) PES and Holter are discordant in assessing efficacy of mexiletine (p < 0.05). (2) Efficacy of mexiletine by Holter criteria is easier to achieve than efficacy by PES. (3) The discordance between the two methods, both with very good reported predictive values, calls for randomized clinical follow-up studies to determine sensitivity and specificity of each method in assessing efficacy of mexiletine.