Background and Aims: AT-rich interactive domain-con-taining protein 1A (ARID1A) is frequently mutated or defi-cient in hepatocellular carcinoma (HCC). However, the role of ARID1A in HCC remains unclear. Therefore, the biological role of ARID1A in HCC was evaluated and a potential mech-anism was investigated. Methods: Arid1a was knocked out in the livers of mice using the CRISPR/Cas9 system delivered by hydrodynamic tail vein injection. The devel-opment of HCC was observed in different mouse models. The correlation of ARID1A and prognosis in patients with HCC was analyzed using cBioPortal. The effect of ARID1A on cell proliferation was assessed by MTT assay following the manipulation of candidate genes. Results: ARID1A de-ficiency alone did not cause HCC in mice, but knockout of ARID1A accelerated liver tumorigenesis in response to di-ethylnitrosamine (DEN) or when a combination knockout of phosphatase and tensin homolog (Pten) plus tumor protein P53 (p53) was introduced. ARID1A mutations were associ-ated with a poorer prognosis in HCC patients. The mRNA level of MYC was significantly higher in patients with an ARID1A mutation compared to those without a mutation. Ectopic expression of ARID1A inhibited HCC cell prolifera-tion. ARID1A knockout increased HCC cell growth and re-sulted in disruptions to DNA damage repair and apoptosis following radiation stress. Furthermore, mechanistic studies revealed that ARID1A inhibited the proliferation of HCC cells via transcriptional down-regulation of MYC. Conclusions: These results describe ARID1A as a tumor suppressor in the liver. A deficiency in ARID1A predicts worse survival in HCC patients and promotes HCC progression via up-regulation of MYC transcription.