<p>Multicentric hepatocellular carcinoma (HCC) often exhibits a heterogeneous inter-nodal response to systemic therapy, leading to reduced therapeutic effectiveness. Here, we report the case of a 70-year-old woman with multicentric HCC treated with atezolizumab plus bevacizumab, followed by lenvatinib. While most nodules responded well to systemic therapy, one nodule at S7 exhibited progression. Distinct from the histology of another nodule that responded to atezolizumab plus bevacizumab, percutaneous ultrasound-guided biopsy of this progressive nodule revealed nuclear positivity for β-catenin. This finding suggested a potential role of β-catenin in immune checkpoint inhibitor resistance. Proton beam therapy was subsequently administered to the resistant lesion, achieving local control. The continuation of immune checkpoint therapy effectively maintained remission of the other nodules, and the patient remained in long-term remission without recurrence. This case indicates the importance of molecular profiling, including β-catenin expression, in cases of multicentric HCC to predict immune checkpoint inhibitor resistance and guide treatment strategies for each nodule. Additionally, it demonstrates the potential of proton beam therapy as a targeted therapeutic approach for immune checkpoint inhibitor-resistant nodules. These findings highlight the possible need for personalized treatment in multicentric HCC by integrating molecular and immunological insights to predict outcomes for complex tumor biology.</p>