T-wave alternans (TWA), an electrophysiologic phenomenon associated with ventricular arrhythmias, is usually detected from selected ECG leads. TWA amplitude measured in the 12-standard and the 3-orthogonal (vectorcardiographic) leads were compared here to identify which lead system yields a more adequate detection of TWA as a noninvasive marker for cardiac vulnerability to ventricular arrhythmias. Our adaptive match filter (AMF) was applied to exercise ECG tracings from 58 patients with an implanted cardiac defibrillator, 29 of which had ventricular tachycardia or fibrillation during follow-up (cases), while the remaining 29 were used as controls. Two kinds of TWA indexes were considered, the single-lead indexes, defined as the mean TWA amplitude over each lead (MTWAA), and lead-system indexes, defined as the mean and the maximum MTWAA values over the standard leads and over the orthogonal leads. Significantly (P < 0.05) higher TWA in the cases versus controls was identified only occasionally by the single-lead indexes (odds ratio: 1.0-9.9, sensitivity: 24-76%, specificity: 76-86%), and consistently by the lead-system indexes (odds ratio: 4.5-8.3, sensitivity: 57-72%, specificity: 76%). The latter indexes also showed a significant correlation (0.65-0.83) between standard and orthogonal leads. Hence, when using the AMF, TWA should be detected in all leads of a system to compute the lead-system indexes, which provide a more reliable TWA identification than single-lead indexes, and a better discrimination of patients at increased risk of cardiac instability. The standard and the orthogonal leads can be considered equivalent for TWA identification, so that TWA analysis can be limited to one-lead system.