Background: The HIMALAYA trial established the combination of durvalumab and tremelimumab (STRIDE) as first-line treatment for advanced hepatocellular carcinoma (HCC). Carbon ion radiotherapy (C-ion RT) allows precise tumor targeting while sparing nearby normal tissue. Our strategy used C-ion RT to target a key tumor with macrovascular invasion (MVI) for disease management and potential MVI control, complemented by STRIDE. Recognising that C-ion RT stimulates immune responses, we posited that merging C-ion RT with STRIDE might enhance therapeutic effects. We present updated data of additional follow-up. 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 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). This analysis of OS was conducted from the additional follow-up data from the primary analysis. 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. The median PFS was a significant 4.67 months (95%CI, 1.35–6.64). At the clinical cut-off date of March 31, 2024, 10 OS events were observed. The median OS was 10.4 months (95% CI, 5.6–15.2), and the 6- and 12-month OS rates were 66.7% and 46.7%, respectively. 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.