Thrombolytic therapy improves survival after acute myocardial infarction (AMI) primarily by preserving left ventricular function. Its influence on the arrhythmogenic substrate remains uncertain. To investigate the electrophysiologic effects of thrombolytic therapy, signal-averaged electrocardiography, endocardial catheter mapping and programmed stimulation were performed in 93 consecutive patients with their first AMI who underwent thrombolytic therapy. Early reperfusion was achieved in 75 patients (group 1), but not in 18 patients (group 2). The incidence of the signal-averaged electrocardiogram abnormality was 11% in group 1 (8 of 75 patients) and 33% in group 2 (6 of 18 patients) (p<0.02). Catheter mapping detected delayed endocardial electrograms in 30 group 1 patients and 10 group 2 patients (p=NS). The spatial distribution of these electrograms was smaller, and the longest duration of endocardial electrograms was shorter in group 1 than in group 2 (p<0.01). Sustained monomorphic ventricular tachycardia was induced less commonly in group 1 (20%) than in group 2 (44%) (p<0.05). In conclusion, thrombolytic therapy can reduce the arrhythmogenic substrate and improve electrical stability after AMI. This antiarrhythmic effect may contribute, in part, to the improved survival of patients treated with thrombolytic drugs.