Methods: A narrative literature review of 107 papers was performed in PubMed. Articles from 2010 and newer were used for clinical data and for classification/scoring system details. The majority of the keywords for searches include the treatment modality name alongside terms such as “HCC”,“multifocal”, or “multinodular”.

Key Content and Findings: Ablation is a curative option for Barcelona Clinic Liver Cancer (BCLC) A disease and is appropriate when liver transplantation (LT) is impractical. It is ideal in disease with≤ 3 nodules (each< 3 cm) preferably confined to one segment. TACE [conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE), balloon-occluded TACE (B-TACE), and less so hepatic arterial infusion chemotherapy (HAIC)] is the major workhorse for multifocal BCLC B disease, in pre-transplant downstaging, and in advanced disease palliation. The Kinki BCLC B subclassification can guide TACE subtype selection. TACE response can be assessed over 2–3 sessions per modified Response Evaluation Criteria in Solid Tumors (mRECIST) and patient session tolerance. TARE is an option for BCLC C disease, with BCLC A/B applications limited by radiation induced liver disease (RILD). Pseudo-ablative techniques like sub-selective TARE (sTARE) are promising but are unproven and less useful in multinodular disease. Finally, combination therapies [TACE+ ablation, liver resection (LR)+ ablation/TACE] are an exciting option but warrant further study.

Conclusions: Multifocal HCC remains challenging to manage. While BCLC is a useful starting point, the patient’s tumor imaging characteristics and clinical circumstances must be considered when selecting the appropriate treatment modality.