Background: Several studies have shown the clinical value of using circulating tumor DNA (ctDNA) for minimal residual disease (MRD) detection, which is more sensitive than traditional imaging methods. However, most MRD detection technologies focus on identifying mutations and require cancer tissue samples. These methods often have limitations, such as high cost, inaccessible cancer tissue, or inability to overcome tumor heterogeneity. SeekInCure is a cost-effective multi-dimensional MRD test that does not require cancer tissue analysis. The purpose of this prospective study was to evaluate the potential broad clinical utility of SeekInCure for detecting MRD in patients with hepatocellular carcinoma (HCC). Methods: 34 HCC patients undergoing radical surgery were prospectively enrolled in this study from Peking University Shenzhen Hospital. Peripheral blood samples of 8 mL were collected before and after surgery and analyzed using the SeekInCure assay, which integrates the protein tumor marker (AFP) and cancer genomic hallmarks: copy number aberrations and fragment size from ctDNA. Patients with positive results for AFP and/or ctDNA in the preoperative/postoperative samples were defined as MRD-positive (MRD+), while negative results were defined as MRD-negative (MRD-). Results: Of the 34 patients, 73.5% (25/34) were in early stages (stages I/II: 61.8%/11.8%), and 61.8% (21/34) received adjuvant therapies. The median follow-up was 279.5 days, ranging from 90 to 1,253 days. 82% (28/34) of the patients had MRD+ results in the preoperative samples, which showed remarkable sensitivity in a cohort with more than 70% of early-stage patients. Our previous findings were confirmed, with preoperative MRD+ patients having worse survival than MRD- patients¹. After radical surgery, 26.5% (9/34) were MRD+. MRD+ patients had worse survival than MRD- patients, with a median overall survival (OS) time of 298 days for MRD+ patients, while the OS time for MRD- patients was not reached (P < 0.01). 6 patients with MRD- in both pre- and post-operative samples had a very favorable outcome (100% OS). Conversely, 9 patients with both positive results had the worst outcome. We also found that MRD- patients receiving adjuvant therapies did not have a survival benefit compared to those without adjuvant therapies, but MRD+ patients receiving adjuvant therapies had better OS than those without adjuvant therapies (P = 0.026). Conclusions: This study confirms the excellent performance of our SeekInCure assay, which does not require cancer tissue analysis, in detecting MRD and the prognostic value of MRD in HCC patients. Adjuvant has no influence on survival, especially in MRD- patients, which indicates that amost one-third of HCC patients do not need additional adjuvant therapy.