OBJECTIVE: Epilepsy and seizures can have dramatic effects on the cardiac function. The aim of this study was to investigate the heart rhythm complexity in patients with drug-resistant epilepsy (DRE). METHODS: Ambulatory 24-h electrocardiograms (ECG) from 70 DRE patients and 50 healthy control subjects were analyzed using conventional heart rate variability (HRV) and multiscale entropy (MSE) methods The variation of complexity indices (CI), which was calculated from MSE profile, was determined. RESULTS: DRE patients had significantly lower time domain (Mean RR, SDNN, RMSSD, pNN50) and frequency domain (VLF, LF, HF, TP) HRV measurements than healthy controls. Of the MSE analysis, MSE profile, CI including Slope 5, Area 1-5, Area 6-15 and Area 6-20 were significantly lower than those in the healthy control group. In receiver operating characteristic (ROC) curve analysis, VLF had the greatest discriminatory power for the two groups. In both net reclassification improvement (NRI) model and integrated discrimination improvement (IDI) models, CI derived from MSE profiles significantly improved the discriminatory power of Mean RR, SDNN, RMSSD, pNN50, VLF, LF, HF and TP. SIGNIFICANCE: The heart rate complexity is impaired for DRE patients. CI are useful to discriminate DRE patients from subjects with normal cardiac complexity. These findings indicate that MSE method may serve as a complementary approach for characterizing and understanding abnormal heart rate dynamics in epilepsy. Furthermore, the CI may potentially be used as a biomarker in monitoring epilepsy.