BACKGROUND: Studies performed before the introduction of fibrinolysis showed that a low heart rate variability (HRV) is associated with higher mortality in post-myocardial infarction (MI) patients. We evaluated whether HRV adds information relevant to risk stratification in patients treated with fibrinolysis as well. METHODS AND RESULTS: From 24-hour ECG recordings obtained at discharge in patients treated with recombinant tissue-type plasminogen activator or streptokinase, we measured several time-domain indexes of HRV: standard deviation (SDNN), root-mean-square of successive differences (RMSSD), and number of RR interval increases > 50 ms ("NN50+"). The prognostic value of HRV for total and cardiovascular mortality was assessed. Of 567 patients with valid recordings, 52 (9.1%) died during the 1000 days of follow-up, 44 (7.8%) of cardiovascular causes. All indexes of low HRV were able to identify patients (16% to 18% of total population) with a higher total mortality (20.8% to 24.2% versus 6.0% to 6.8%, depending on index used). The independent predictive value of low HRV was confirmed by the adjusted analysis with the following relative risks: NN50+, 3.5 (95% CI, 1.9 to 6.7); SDNN, 3.0 (95% CI, 1.55 to 5.9); and RMSSD, 2.8 (95% CI, 1.5 to 5.3). Advanced age, previous MI, Killip class at entry, and use of digitalis were also independent predictors. Similar data were obtained for cardiovascular mortality. CONCLUSIONS: Time-domain indexes of HRV retain their independent prognostic significance even in post-MI patients of all ages treated with fibrinolysis.