While deemed potentially curative, surgical resection of hepatocellular carcinoma (HCC) is associated with >70% risk of post-operative relapse. Recurrence is uniquely multifactorial in HCC, potentially stemming from metachronous re-occurrence of the original tumor or de novo cancerization. Circulating tumor DNA may improve personalized risk stratification post-resection, a setting where adjuvant immunotherapy has failed to provide survival benefits.