Simple SummaryThe combination of atezolizumab plus bevacizumab (Atz/Bev) is now widely used in clinical practice as a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the established regimen for post-treatment after Atz/Bev is unknown. We investigated the efficacy and safety of cabozantinib in patients previously treated with Atz/Bev in real clinical practice, with a focus on whether patients met criteria of Child–Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. Our results suggest that cabozantinib in patients with advanced HCC previously treated with Atz/Bev can be expected to yield similar outcomes to those seen in the CELESTIAL trial conducted using cabozantinib for post-sorafenib treatment if patients have good liver function and are in good general condition.Abstract(1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child–Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. (2) Methods: Eleven patients (57.9%) met the criteria of both Child–Pugh class A and ECOG-PS score 0/1 (CP-A+PS-0/1 group) and eight patients (42.1%) did not (Non-CP-A+PS-0/1 group); efficacy and safety were retrospectively evaluated. (3) Results: Disease control rate was significantly higher in the CP-A+PS-0/1 group (81.1%) than in the non-CP-A+PS-0/1 group (12.5%). Median progression-free survival, overall survival and duration of cabozantinib treatment were significantly longer in the CP-A+PS-0/1 group (3.9 months, 13.4 months, and 8.3 months, respectively) than in the Non-CP-A+PS-0/1 group (1.2 months, 1.7 months, and 0.8 months, respectively). Median daily dose of cabozantinib was significantly higher in the CP-A+PS-0/1 group (22.9 mg/day) than in the non-CP-A+PS-0/1 group (16.9 mg/day). (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function (Child–Pugh A) and are in good general condition (ECOG-PS 0/1).