Background: The HIMALAYA study established the efficacy and safety of durvalumab combined with tremelimumab (STRIDE) as a first-line treatment for advanced hepatocellular carcinoma (HCC). Carbon ion radiotherapy (C-ion RT), a type of particle therapy, allows precise tumor targeting while sparing nearby normal tissue. In HCC, macrovascular invasion (MVI) signifies aggressive progression with poor outcomes. Our strategy used C-ion RT to target a key tumor with MVI for disease management and potential MVI control, complemented by STRIDE. Recognizing that radiation therapies, including C-ion RT, stimulate immune responses, notably releasing tumor antigens and DAMPs (immune priming), we posited that merging C-ion RT with STRIDE might enhance therapeutic effects. Methods: This is a Phase Ib, multicenter study evaluating durvalumab with particle beam radiotherapy in HCC patients with MVI (Cohort A) and STRIDE (Cohort B). Both cohorts began with patients resistant to standard treatments. After safety confirmation, the study expanded to include systemic therapy-naïve patients, totaling 15. C-ion RT begins after day 8 of the first cycle, following the initial drug dose. The relative biological effectiveness weighted dose is set at 60 Gy in four fractions over one week, targeting one representative intrahepatic nodule with MVI. The primary endpoint is adverse event rates, including dose limiting toxicity (DLT), with secondary endpoints on progression free survival (PFS) and overall survival (OS) (jRCT2031210046). Results: From July 2021 to January 2023, 15 advanced HCC patients were enrolled in our study (Cohort A: 3, Cohort B: 12). Four in Cohort B were systemic therapy-naïve. All cases confirmed MVI radiologically; with tumor invasion observed in the main portal vein for 4 patients and in the inferior vena cava for one. DLT evaluations in 3 from each cohort showed no incidents. While Cohort A had no adverse events, 4 patients in Cohort B (26.7%) experienced serious treatment-related adverse events. Cohort B's median PFS was a significant 2.79 months (95%CI, 1.12–6.64). The 6- and 12-month PFS rates stood at 38.1% and 12.7% respectively. The median OS is still undetermined, but promisingly, the 6- and 12-month survival rates both reached 87.5%. Conclusions: The safety of STRIDE in combination with particle therapy has been confirmed in advanced HCC with MVI. This combination, especially the irradiation of tumors with MVI using C-ion RT, holds promise in managing prognostic determinant tumors and potentially enhancing OS. Clinical trial information: jRCT2031210046.