Background: Mutations in TP53 and CTNNB1 are common in early stage HCC resection samples. The frequency and prognostic impact of these mutations in advanced HCC is not known. We conducted this retrospective analysis using a large NGS panel to explore for association between tumor genetics, clinicopathologic features, and prognosis in an advanced HCC cohort. Methods: Eligible cases had diagnosis of unresectable HCC or mixed HCC-cholangiocarcinoma and were enrolled on NCT01008917 or NCT01687673 clinical trials of sorafenib plus temsirolimus with informed consent for specimen banking for future research including genetic testing. Paired tumor and germline (blood) DNA samples were sequenced using a capture-based NGS cancer panel to allow for determination of somatic variants. Analysis was based on the human reference sequence UCSC build hg19. Variants were called using GATK Unified Genotyper software. Somatic, non-synonymous, and exonic calls were curated using COSMIC, cBioPortal, and Pubmed. Results: Cases with HCC (n = 21) and mixed HCC-cholangiocarcinoma (n = 2) comprised the cohort (N = 23). Male/female: 83%/17%. Race: White 56%, Asian 39%. BCLC stage: B 35%, C 65%. Etiology: HBsAg+ 26%, HCV+ 39%. Immune infiltrates ( ≥ 1 on scale 0-3) were present in 7/12 (58%) evaluable tumor samples. TP53 mutations were present in 14/23 (61%, 95% CI: 38.5, 80.0). CTNNB1 mutations were present in 7/23 (30%, 95% CI: 13.2, 52.9). There was no significant difference between HBsAg+ and HCV+. Both TP53 and CTNNB1 mutation were present in 4/23 (17%). CTNNB1 mutation was present in 2/7 (29%) cases with immune infiltrate score ≥ 1, and 1/5 (20%) with score < 1 (not significant). Other mutations and variants will be reported. Conclusions: NGS in this advanced HCC cohort suggests a higher incidence of TP53 and coexisting TP53 plus CTNNB1 mutations than has been reported in early stage HCC which requires confirmation in a larger cohort. There was no clear relationship between these mutations, HCC etiology, or tumor immune infiltrates though interpretation is limited by small sample sizes. Analyses are ongoing to explore for association between TP53 and CTNNB1 mutations and prognosis in this advanced HCC cohort.