Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable HCC, but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. Methods: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intra-abdomen based on a radiological evaluation adopted from RECIST v 1.1. Up to 2 lesions were chosen as target lesions in each organ for the organ-specific response evaluation. Results: The median age was 60 years. The majority of study patients were male in both groups (83.4% and 85.8% in the atezolizumab-bevacizumab and lenvatinib groups, respectively). The etiology of HCC was similar between the two groups: hepatitis B virus infection was the most common etiology in both groups (73.3% and 65.7% in the atezolizumab-bevacizumab and lenvatinib groups, respectively), while 21.2% and 29.0% of patients had non-viral HCC, respectively. Extrahepatic spread was identified in 76.0% and 74.6% of patients in the atezolizumab-bevacizumab and lenvatinib groups, respectively: lung, LN, and intra-abdominal metastases were present in 39.6% vs. 39.1%, 30.0% vs. 33.1% and 16.6% vs. 15.4% of patients, respectively. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was higher overall in the atezolizumab-bevacizumab group than in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9%, and 33.3% vs. 15.0% for intrahepatic, lung, LN and intra-abdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6% and 36.0% vs. 12.5%, respectively. Among patients with a non-viral etiology, atezolizumab-bevacizumab was not clearly associated with a better organ-specific response for the LN and intra-abdominal lesions: 20.0% vs. 54.5% and 20.0% vs. 25.0%, respectively, for a ≥ 30% reduction in the tumor burden. Conclusions: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.