Recently, heart rate variability (HRV) analysis has been used as an indicator of epileptic seizures. As women have a lower sudden, unexpected death in epilepsy risk and greater longevity than men, the authors postulated that there are significant gender-related differences in heart rate dynamics of epileptic patients. The authors analyzed HRV during 5-minute segments of continuous electrocardiogram recording of age-matched populations. The middle-aged epileptic patients included males (n = 12) and females (n = 12), ranging from 41 to 65 years of age. Relatively high- (0.15 Hz-0.40 Hz) and low-frequency (0.01 Hz-0.15 Hz) components of HRV were computed using spectral analysis. Poincaré parameters of each heart rate time series were considered as nonlinear features. The mean heart rate markedly differed between gender groups including both right- and left-sided seizures. High-frequency heart rate power and the low-frequency/high-frequency ratio increased in the pre-ictal phase of both male and female groups (p < .01), but men showed more increase especially in right-sided seizures. The standard deviation ratio, SD2/SD1, of pre-ictal phase was greater in males than females (p < .01). High-frequency spectral power and parasympathetic activity were higher in the female group with both right- and left-sided seizures. Men showed a sudden increase in sympathetic activity in the pre-ictal phase, which might increase the risk of cardiovascular disease in comparison to women. These complementary findings indicate the need to account for gender, as well as localization in HRV analysis.