BACKGROUND: Patients with chronic Chagas cardiopathy (CCC), which may be associated with cardiac arrhythmias, frequently use amiodarone, an antiarrhythmic drug that, experimentally, appears to modulate the cardiac autonomic function. OBJECTIVE: The present cross-sectional observational study aimed to evaluate autonomic cardiac modulation in patients with CCC undergoing chronic amiodarone therapy. METHODS: Three groups were investigated: Group 1 included patients with CCC not treated with amiodarone (n = 27); Group 2 included patients with CCC with prolonged use (at least 6 months) of amiodarone (n = 16); and Group 3 included non-Chagasic control patients (n = 23). All patients underwent a complete clinical and laboratory assessment, followed by autonomic function tests, consisting of a basal continuous electrocardiogram in the resting supine position for 10 minutes, followed by a change the orthostatic posture for a further 5 minutes. Heart rate variability (HRV) parameters (median and interquartile interval) were quantified using linear methods in the time- and frequency-domains (autoregressive spectral analysis) and nonlinear methods, including symbolic analysis. RESULTS: Patients with CCC using amiodarone had changes in HRV suggestive of an offset in the sympatho-vagal balance with a vagal modulation predominance (normalized HF, 49.7[27.4] vs 31.1[22.8] [P < 0.05]; and percentage 2V, 40.1 [14.6] vs 21.5 [13.4] [P < 0.05] vs untreated CCC group). These changes were further accompanied by increases in parameters indicative of greater complexity of HRV. CONCLUSIONS: The deviation in the sympatho-vagal balance and the increase in the complexity of HRV strongly suggest that amiodarone may have a cardioprotective effect, in addition to its antiarrhythmic effects, which could increase the survival of these patients.