There is lack of prospective evidence regarding vagal nerve stimulator (VNS) in younger children with intractable epilepsy. Here, we report the outcomes of using VNS in two pre-school patients for pediatric intractable epilepsy (VNS-PIE) study. Medical treatment was ineffective in both the patients, and they underwent VNS implantation. Seizure frequency, score on the Gesell scale, and heart rate variability (HRV) were assessed following VNS therapy. After 6 months VNS treatment, the seizure frequency in the two patients decreased by 50% from that at baseline, based on the records in their epileptic diary. Video electroencephalography (EEG) examinations showed that abnormal fast waves diminished in the background in Patient 1, and captured seizure frequency in Patient 2 remarkably decreased. The adaptability, language, and individual and social interaction on their Gesell scales increased slightly, suggesting that VNS had a positive effect on the development of these two children. Moreover, the changes in the different HRV indices indicated improved cardiac autonomic function. In conclusion, these two cases indicated that VNS may not only be a superior therapy for pre-school children with intractable epilepsy, but also may exert a positive effect on their mental development and cardiac autonomic function.