Epithelial ovarian cancer (EOC) is a lethal form of gynecological malignancy. Some EOC patients experience relapse after standard primary debulking surgery (PDS) and adjuvant chemotherapy (ACT). Identifying molecular residual disease (MRD) by circulating tumor DNA (ctDNA) detection can timely signal the potential for relapse. However, research on the usage of ctDNA for MRD detection in EOC is limited.Fifty-one EOC patients who received standard PDS and ACT were included. Targeted sequencing based on a panel of 1021 cancer-related genes, along with further validation using Enrich-rare-mutation sequencing, was performed on tumor tissues acquired during PDS and on plasma samples collected before and after PDS/ACT to identify variants reflecting tumor signals.Post-surgery MRD was associated with relapse (Log-rank p = 0.0006) and was identified as an independent prognostic factor (HR, 3.4; 95% CI, 1.02-11.42; p = 0.047). The negative and positive predictive values were 0.83 and 0.62 respectively. Additionally, post-surgery MRD outperformed CA125 in predicting relapse, and integrating both parameters could provide more accurate risk stratification. Post-ACT MRD detection identified the patients with ctDNA clearance who were still at risk of relapse. Furthermore, baseline ctDNA detection could help determine patients who are not suitable for further tests after surgery.Post-surgery MRD is superior to CA125 in predicting relapse in EOC. Patients exhibiting transient ctDNA clearance, as evaluated by post-ACT MRD, may require longitudinal monitoring. Baseline ctDNA detection could help determine whether post-surgery ctDNA monitoring should be performed.© 2024. The Author(s).