BACKGROUND: Major adverse cardiovascular events (MACE) constitutes the main cause of morbidity and mortality in ischemic heart failure (HF) patients. The prognostic value of the autonomic nervous system parameters and microvolt T-wave alternans (MTWA) in this issue has not been identified to date. The aim herein, was to assess the usefulness of the abovementioned parameters in the prediction of MACE in HF patients with left ventricular systolic dysfunction of ischemic origin. METHODS: Baroreflex sensitivity (BRS), heart rate variability (HRV), MTWA and other well-known clinical parameters were analyzed in 188 ischemic HF outpatients with left ventricular ejection fraction (LVEF) </= 50%. During 34 (14-71) months of follow-up, 56 (30%) endpoints were noted. RESULTS: Univariate Cox analyses revealed BRS (but not HRV), MTWA, age, New York Heart Association functional class III, LVEF, implantable cardioverter-defibrillator presence, use of diuretics and antiarrhythmic drugs, diabetes, and kidney insufficiency were defined as significant predictors of MACE. Pre-specified cut-off values for MACE occurrence for the aforementioned continuous parameters (age, LVEF, and BRS) were: >/= 72 years, </= 33%, and </= 3 ms/mmHg, respectively. In a multivariate Cox analysis only BRS (HR 2.97, 95% CI 1.35-6.36, p < 0.006), and LVEF (HR 1.98, 95% CI 0.61-4.52, p < 0.038) maintained statistical significance in the prediction of MACE. CONCLUSIONS: Baroreflex sensitivity and LVEF are independent of other well-known clinical parameters in the prediction of MACE in patients with HF of ischemic origin and LVEF up to 50%. BRS </= 3 ms/mmHg and LVEF </= 33% identified individuals with the highest probability of MACE during the follow-up period.