Background: Emerging data suggest that circulating tumor DNA (ctDNA) could detect minimal residual disease (MRD) and reflect tumor recurrence after radical resection in hepatocellular carcinoma (HCC). However, most reported ctDNA measurements are based on hotspot mutations and their predictive value in liver transplantation (LT) are still undetermined. We conducted a pilot study investigate ctDNA fingerprint as the detection marker of MRD in HCC patients undergoing LT. Methods: We enrolled 74 patients in HCC and monitored their ctDNA changes along the course of treatment at both pre- and post-operation by serial sampling of peripheral blood. All of the patents were treated by LT, and their ctDNA variations were used to assess the recurrence. We analyzed the correlation between ctDNA levels and recurrence-free survival (RFS) of the patients. Results: We monitored the ctDNA value of each patient before and after LT and found that the ctDNA-positive group was associated with higher recurrence rate (31.7% vs 11.5%), and has a shorter RFS than that of the ctDNA-negative group at baseline (preopreation) (HR, 3.25; CI 95% 1.18-8.97; p = 0.019). The conclusion also stands in patients at first timepoint follow-up after LT (postoperation) (recurrence rate, 46.2% vs 21.3%; HR, 4.26; CI 95% 1.62-11.2; p = 0.010). Moreover, changes of ctDNA were associated with RFS during the course after LT, both the ctDNA-decreased group and ctDNA-negative group have favorable clinical benefit than ctDNA-increased group. Conclusions: This study confirming the association between baseline levels of ctDNA and RFS in HCC undergoing LT. More importantly, it suggests the change of ctDNA level in plasma is a promising biomarker of MRD detection and patient prognosis in early HCC.