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Aim: Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is used as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). Serious adverse events (AEs), including rupture of esophagogastric varices, have been seen during treatment. Therefore, the relationships of efficacy, safety, and portal hypertension (PH) were analyzed., Methods: A total of 146 patients with u-HCC and Child-Pugh Scores of 5-7 received Atezo + Beva. Prophylactic treatment for varices was performed for patients with the risk of rupture of varices before the start of Atezo + Beva. A propensity score-matched cohort was created to minimize the risk of potential confounders. Efficacy was assessed in 41 propensity score-matched pairs. AEs were assessed between patients without PH (n = 80) and with PH (n = 66)., Results: In patients without PH and with PH, median overall survival was 18.4 months and 18.8 months (p = 0.71), and median progression-free survival was 8.6 months and 5.8 months (p = 0.92), respectively. On the best radiological response evaluation for Response Evaluation Criteria in Solid Tumors, the objective response rate was 31.7% and 26.8% (p = 0.81), respectively. Variceal rupture occurred in three patients with PH, but there were no significant differences in the occurrence of variceal rupture (p = 0.090) and Grade 3-4 AEs between patients without and with PH., Conclusions: No significant differences in efficacy and safety were observed with PH. Prophylactic treatment for varices before the start of Atezo + Beva would allow treatment to continue relatively safely., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)