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Background Proton radiotherapy has emerged as a promising local treatment for hepatocellular carcinoma (HCC). This study examined the clinical outcomes of proton radiotherapy alone compared with its combination with immunotherapies (Proton-IO) or tyrosine kinase inhibitors (Proton-TKI) in patients with intermediate- to advanced-stage HCC.Methods We retrospectively reviewed the medical records of 137 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC treated with proton radiotherapy at Linkou Chang Gung Memorial Hospital between 2020 and 2023. Patients were stratified into three groups: proton radiotherapy alone (n = 64), Proton-IO (n = 44), and Proton-TKI (n = 29). The most frequently used immuno-oncology agents were atezolizumab-bevacizumab (n = 33) and pembrolizumab (n = 5). Tyrosine kinase inhibitors (TKIs) included lenvatinib (n = 16) and sorafenib (n = 13).Results With a median follow-up of 30 months, patients in the Proton-IO group exhibited significantly improved overall survival (OS) compared to those receiving Proton-TKI or proton radiotherapy alone (3-year OS: 71.5% vs. 41.3% vs. 42.4%; P = 0.002). Proton-IO was also associated with superior time to progression (TTP) and distant metastasis-free survival (DMFS) (3-year TTP: 50.5% vs. 22.4% vs. 24.2%, P = 0.003; 3-year DMFS: 83.4% vs. 40.7% vs. 60.1%, P = 0.027). Local control (LC) did not significantly differ among the groups (3-year LC: 97.7% vs. 92.9% vs. 86.8%; P = 0.230). Multivariate analysis identified Proton-IO as an independent predictor of improved OS (P <0.001), TTP (P <0.001), and DMFS (P = 0.004). Grade 3–4 upper gastrointestinal (UGI) bleeding was observed in two (1.5%) patients (proton monotherapy, n = 1; Proton-IO, n = 1). There were no significant differences among the groups in the incidence of UGI bleeding, liver toxicity, colitis, rib fractures, or hematologic adverse events.Conclusions Proton radiotherapy combined with immunotherapies was well-tolerated and significantly associated with improved OS, TTP, and DMFS in patients with BCLC stage B or C HCC, compared to proton radiotherapy alone or in combination with TKIs.Ethics Approval This study protocol was reviewed and approved by the Institutional Review Board of the Chang Gung Medical Foundation (approval number: 202401750B0C5001).