Background: Hepatocellular carcinoma (HCC) is a leading cause of mortality, with Hepatitis B virus (HBV) infection as a dominant etiology. Surgery or ablation may be curative for early-stage HCC. Thus, effective detection strategies are needed. We investigated genomic aberrations in circulating tumor DNA (ctDNA) as a potential diagnostic marker of HCC in HBV-infected patients. Methods: We identified early stage (BCLC 0-A) HCC cases (n = 21) and cancer-free controls (n = 15) from a cohort of Asian patients with HBV, undergoing surveillance at Thomas Jefferson University Hospital between 2013-2017. Blood samples were collected. Circulating cell-free DNA was isolated from plasma and assayed by capture-based next-generation sequencing of a targeted panel of 23 genes implicated in HCC pathogenesis. Sequencing data analysis and somatic mutation identification were conducted using a computational pipeline. Using area under the curve (AUC) in receiver operating characteristic analysis, we evaluated gene alterations and clinical factors (age, gender, cirrhosis) in an exploratory early detection HCC model. Results: Mutant ARID1A, ATM, CDKN2A, CTNNB1, ERBB2, TP53 genes were increased in HCC cases relative to non-cancer patients (85.7% vs 53.3%, P = 0.058; 42.9% vs 6.7%, P = 0.025; 38.1% vs 6.7%, P = 0.051; 42.9% vs 0%, P = 0.005; 52.4% vs 13.3%, P = 0.016; 100% vs 66.7%, P = 0.008, respectively). HCC patients had higher prevalence of cirrhosis than controls (90.5% vs. 60%, P = 0.046). Using the 6 mutant genes alone, the AUC for discriminating HCC from non-cancer patients was 0.827 (95% confidence interval [CI]: 0.701-0.953), which was greater than the AUC for discriminating cirrhosis from non-cirrhosis (0.531). When the 6 mutant genes were combined with clinical factors, the AUC of the exploratory HCC detection model increased to 0.914 (P= 0.045). Conclusions: We identified 6 genomic aberrations in ctDNA that were more prevalent in HCC patients compared with non-cancer patients. Combining these alterations with clinical factors may identify HCC in HBV-infected patients at an early stage. These findings warrant further validation in future studies.