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Belal Abousaida,1,* Danushka Seneviratne,1,* Bradford S Hoppe,1 Stephen J Ko,1 Aroumougame Asaithamby,2 Francis A Cucinotta,3 Jessica M Kirwan,4 Kabir Mody,5 Beau Toskich,6 Jonathan B Ashman,7 Christopher L Hallemeier,8 Sunil Krishnan1 1Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3School of Integrated Health Sciences, University of Las Vegas, Las Vegas, NV, USA; 4Department of Radiation Oncology, University of Florida, Gainesville, FL, USA; 5Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clinic Florida, Jacksonville, FL, USA; 6Division of Interventional Radiology, Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA; 7Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA; 8Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, MN, USA*These authors contributed equally to this workCorrespondence: Sunil KrishnanDepartment of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USATel +1 713-202-8063Email krishnan.sunil@mayo.eduAbstract: Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.Keywords: carbon ion therapy, hepatocellular carcinoma, hypofractionation