Background: Vagus nerve stimulation (VNS) is an effective treatment for patients with refractory epilepsy, yet with varied predictive factors and heterogeneous long-term outcomes. Adjustment of VNS parameters is critical for obtaining favorable efficacy. In this study, we aimed to investigate the long-term outcomes and the possible predictive factors of VNS in patients with refractory epilepsy.Methods: Eighty-six patients (59 males and 27 females) who underwent VNS implantation for treatment of refractory epilepsy between May 2016 and May 2017 at five Epilepsy Centers were enrolled. The clinical data, including sex, age at epilepsy onset, VNS implantation, epilepsy duration, seizure type, MRI findings, history of neurosurgical operations, and responder rate (responders were those with >= 50% seizure reduction), were analyzed.Results: Four-year follow-up data were available for 76 patients (53 males and 23 females). The mean current intensity at the last follow-up was 1.8 +/- 0.3 mA (range: 0.75-2.5 mA). The mean seizure reduction was 36.2% at 6 months, 38.5% at 1 year, 69.4% at 3 years, and 56.7% at 4 years. A favorable outcome of >= 50% reduction in seizure frequency occurred in 40.0% of the patients at 6 months, 55.9% at 1 year with 4 patients being seizure-free, 63.2% at 3 years with 5 patients being seizure-free, and 68.4% at 4 years with 5 patients being seizure-free. Earlier onset age (P < 0.001) and shorter duration (P = 0.042) were associated with favorable prognosis. Compared with generalized tonic-clonic seizures, tonic seizures had a favorable outcome (P = 0.026). Twenty-three patients underwent neurosurgical operations before VNS implantation, and the responder rate was 60.9% at the last follow-up.Conclusions: VNS is an adjunctive and effective treatment for patients with refractory epilepsy who are not good candidates for surgical resection or have failed to respond to surgical treatment. The stimulation efficacy increases over time after implantation, and earlier exposure to VNS improves the prognosis.