Background/aim <p>Hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRLM) carry high recurrence rates after surgery or transplantation. Conventional imaging and biomarkers have limited sensitivity for detecting minimal residual disease (MRD). Circulating tumor DNA (ctDNA) is a promising biomarker that may enable earlier recurrence detection compared with standard methods. The aim of this randomized controlled trial is to evaluate the clinical utility of ctDNA monitoring in the early detection of disease recurrence and its impact on monitoring progression in patients undergoing liver resection or transplantation for HCC and CRLM.</p> Methods <p>This randomized, controlled trial will enroll 300 patients undergoing liver resection or transplantation for CRLM or HCC. Participants will be randomized 2:1 to ctDNA monitoring or standard follow-up. ctDNA will be analyzed at three predefined time points (baseline, 1 month, and 6 months postoperatively) and compared with tumor tissue mutation profiles generated by next-generation sequencing (NGS). All patients will be followed for 24 months with imaging, tumor markers, and quality-of-life assessments. The primary endpoint is ctDNA-defined recurrence. Secondary endpoints include recurrence-free survival, overall survival, time to recurrence detection, patient-reported outcomes, and cost-effectiveness.</p> Discussion <p>This study will assess whether ctDNA-guided monitoring enables earlier recurrence detection and improves clinical decision-making after liver resection or transplantation. Incorporating ctDNA into surveillance may support earlier therapeutic intervention, optimize follow-up strategies, and enhance long-term outcomes.</p> Trial registration <p>ClinicalTrials.gov NCT07001085. Registered on 2025.</p>