Background: To prospectively evaluate the efficacy and safety of a ketogenic diet (KD) in managing seizures in children with drug-resistant epilepsy and identify factors influencing its efficacy in a Chinese cohort. Methods: Ninety-two pediatric patients (55 males, 37 females), aged 3 months to 10 years (29.26±24.18 months), with drug-resistant epilepsy who followed a KD for 1-12 months were included. The efficacy of the KD was evaluated by assessing the seizure frequency, as reported by parents/caregivers. The effects of demographic and clinical variables on patients’ duration on the KD were analyzed.Results: At the 1-, 3-, 6-, and 12-month follow-ups, 78.26%, 75%, 80%, and 93.10% of patients were responsive to KD therapy, respectively. Five non-responders at 3 months became responsive by 6 months. Age, disease duration, seizure type, etiology, anti-epileptic drug (AED) type, and KD ratio did not affect treatment efficacy. After the KD, changes in AEDs and electroencephalography and imaging findings were statistically significant (p<0.05). Only 4.34% patients experienced complications requiring medical intervention. Conclusions: KD is an effective and well-tolerated therapy for children with drug-resistant epilepsy. The KD adherence rate largely depends on its efficacy. Genetic information relating to the diet response and synergistic effect between KD and AEDs requires further study. Clinical trial has registered at Chinese clinical trial registry: http://www.chictr.org.cnRegistration numbers: ChiCTR2000031394. Date: (30/03/2020)Availability of data and material: http://www.medresman.org.cn/uc/index.aspxCode availability (software application or custom code): ziyan030815, wangjuan030815