AIMS: In March 2024, the American Society of Clinical Oncology recommended the combination of tremelimumab plus durvalumab as a treatment for advanced hepatocellular carcinoma (HCC). Although safety data for first-line treatments are available, information on adverse events related to late-line treatments is limited. This study aimed to identify risk factors for adverse events in patients who received this combination. METHODS AND RESULTS: We conducted a retrospective cohort study from March 2023 to January 2025 at Yokohama City University Hospital, involving 24 patients aged 18 years or older with unresectable HCC. All 24 patients experienced at least one adverse event during treatment. Of these, the incidence of treatment-related adverse events leading to treatment discontinuation after tremelimumab plus durvalumab therapy was 50.0% (12/24). In the discontinuation group, prior atezolizumab plus bevacizumab therapy (66.7% vs. 16.7%,  = 0.036) was more frequent than in the continuation group. CONCLUSION: In patients with unresectable HCC who received tremelimumab plus durvalumab, the risk of treatment-related adverse events was associated with prior atezolizumab plus bevacizumab therapy. These factors may increase the likelihood of developing treatment-related adverse events.