Background: HCC is often diagnosed based on high-quality cross-sectional imaging, and when a biopsy is pursued, acquisition of tissue may be of limited quantity and quality or complicated by underlying medical comorbidities. NGS of tumor derived circulating cfDNA represents an investigational tool for non-invasive molecular profiling, that has the potential to aid in diagnosis, prognosis, and in monitoring disease status. Although prior reports have evaluated such technologies, few studies have included tumor tissues to confirm histology and to explore plasma-tissue gene concordance. Methods: The primary objective of this retrospective cohort study was to define genomic alterations in circulating cfDNA and to explore plasma-tissue genotype concordance in HCC pts. HCC pts underwent collection of cfDNA for NGS using the MSK-ACCESS 129-gene assay between August 2019 and February 2021. Matched tissue-based NGS with the FDA authorized MSK-IMPACT gene assay was completed when tumor tissue was available. Clinical actionability of sequence variants was annotated by OncoKB, an FDA recognized knowledge base. Clinicopathologic characteristics were extracted, and all data were reported with descriptive statistics. Results: 51 unique patients with 53 plasma samples had an HCC histological diagnosis. Pts were male (39, 76%), median age 69 (42-87), viral hepatitis-related (24, 47%), and advanced stage (Stage III:9, 18%; Stage IV:38, 74.5%). Extrahepatic disease and macrovascular involvement were observed in 28 (55%) and 19 (38%) pts, respectively. 22 (43%) pts had AFP ≥400 ng/mL. 49 (92.5%) of 53 plasma samples had detectable genomic alterations. Median cfDNA yield after extraction was 39.43 ng (range: 7.93-287.68). The most frequently mutated genes occurring in > 10% of patients were TERT (57%), TP53 (47%), CTNNB1 (37%), ARID1A (18%) and TSC2 (14%). The most common oncogenic pathways that contained alterations were WNT-β-Catenin (45%) and PIK3-AKT-TOR (25%). 37 (73%) pts underwent tissue sequencing with MSK-IMPACT with a median time of 9.0 months to the time cfDNA testing. MSK-ACCESS identified mutations observed in tumor in most cases: TERT (20/22; 91%), TP53 (16/17; 94%), CTNNB1 (11/12; 92%), ARID1A (6/6; 100%) and TSC2 (6/7; 86%). In 18 (49%) of 37 paired samples, additional mutations in cfDNA not seen in tumor were detected and included KRAS, EGFR, and TP53 alterations. Potentially actionable mutations were identified through cfDNA in 37% of cases including TSC1/2 (18%), BRCA1/2 (8%) and PIK3CA (8%). Conclusions: Circulating cfDNA genotyping with MSK-ACCESS identifies previously reported HCC tumor genomic profiles and revealed tumor-associated mutations in 92.5% of plasma samples. Ongoing efforts will explore predictive and prognostic implications of NGS at different HCC stages as well as kinetics of treatment response.