Corpus callosotomy (CC) is appropriate for patients with seizures of a bilateral or diffuse origin, or those with seizures of a unilateral origin with rapid spread to the contralateral cerebral hemisphere. The efficiency of CC in patients with drug-resistant epilepsy is a long-term concern because most articles reporting the surgical results of CC arise from small case series, and the durations of follow-up vary.PubMed, Embase, Cochrane Library, and Web of Science were searched to identify papers published before November 8, 2021. The systematic review was completed following PRISMA guidelines. Outcomes were analyzed by meta-analysis of the proportions.A total of 1644 patients with drug-resistant epilepsy (49 retrospective or prospective case series studies) underwent CC, and the follow-up time of all patients was at least 1 year. The rate of complete seizure freedom (SF) was 12.38% (95% confidence interval [CI], 8.17%-17.21%). Meanwhile, the rate of complete SF from drop attacks was 61.86% (95% CI, 51.87%-71.41%). The rates of complete SF after total corpus callosotomy (TCC) and anterior corpus callosotomy (ACC) were 11.41% (95% CI, 5.33%-18.91%) and 6.75% (95% CI, 2.76%-11.85%), respectively. Additionally, the rate of complete SF from drop attacks after TCC was significantly higher than that after ACC (71.52%, 95% CI, 54.22%-86.35% vs. 57.11%, 95% CI, 42.17%-71.49%). The quality of evidence for the three outcomes by GRADE assessment was low to moderate.There was no significant difference in the rate of complete SF between TCC and ACC. TCC had a significantly higher rate of complete SF from drop attacks than did ACC. Furthermore, CC for the treatment of drug-resistant epilepsy remains an important problem for further investigation because there are no universally accepted standardized guidelines for the extent of CC and its benefit to patients. In future research, we will focus on this issue.© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.