This study aimed to compare heart rate variability (HRV) in patients with drug-resistant mesial temporal lobe epilepsy (MTLE) with healthy controls and to analyze their clinical and sociodemographic variables predictive for HRV. Thirty-nine consecutive patients with drug-resistant MTLE were included in the study. The control group included twenty-seven healthy participants matched by age and gender. Seven HRV indices (HR, RR, rMSSD, SDNN, LF, HF, and LF/HF) were compared between patients and controls. The clinical and sociodemographic variables independently associated with the HRV indices were identified by multiple linear regression. In comparison with controls, the patients with MTLE showed a significant reduction in RR, rMSSD, SDNN, LF, HF, and LF/HF indices (t value 1.97-5.97, p鈥?鈥?.05). Multiple regression models showed that disease duration predicted 11-22% of the analyzed HRV indices. Time domain indices showed higher association with disease duration than coefficients in frequency domain. Patients with drug-resistant MTLE present cardiac autonomic tone dysfunction, showing a significant reduction in their HRV indices (RR, SDNN, rMSSD, LF, HF, and LF/HF). Disease duration has a negative association with all HRV indices. This study contributes to understanding the relationship between MTLE and the cardiac autonomic tone, with possible implications for sudden unexpected death in epilepsy.