543 Background: The Check-Mate 9DW trial demonstrated that combining ipilimumab with nivolumab (Ipi/Nivo) improved survival outcomes compared with sorafenib or lenvatinib in advanced hepatocellular carcinoma (aHCC). Accumulated evidence suggests that immune checkpoint inhibitor (ICI) monotherapy elicits limited intrahepatic responses in patients with aHCC. Here, we aimed to examine the organ-specific objective response rate (OSORR) of Ipi/Nivo compared with that of nivolumab monotherapy (Nivo) and to evaluate the OSORR of Ipi/Nivo based on the prior use of ICI treatment. Methods: We conducted a retrospective assessment of 69 Ipi/Nivo-treated patients and 164 nivolumab-treated patients for aHCC at five referral hospitals in Korea. Only patients classified as Child-Pugh Class A were included. Organ-specific response criteria were adopted from RECIST 1.1, according to the indicated primary sites, including the liver, lungs, lymph nodes and other sites of metastasis. Results: Baseline characteristics of the Ipi/Nivo and Nivo groups were comparable. However, 65.2% of patients in the Ipi/Nivo group had prior ICI exposure, compared with only 4.3% in the Nivo group. The objective response rate (ORR) of Ipi/Nivo was 29.0%. The Ipi/Nivo combination therapy elicited OSORRs for 204 individual lesions: 18.0% in the liver, 17.7% in the lungs, 30.0% in the lymph nodes, and 12.5% in other sites. Within the Ipi/Nivo group, the ORR was 45.8% for patients without prior ICI exposure and 20.0% for those with prior ICI exposure. Patients without prior ICI exposure demonstrated OSORRs for 72 individual lesions: 29.0% in the liver, 31.3% in the lungs, 33.3% in the lymph nodes, and 23.1% at other sites. Conversely, patients with prior ICI exposure exhibited OSORRs for 132 individual lesions: 11.5% in the liver, 11.4% in the lungs, 27.8% in the lymph nodes, and 7.4% at other sites. Patients who exhibited a response in one organ were more likely to demonstrate responses in other organs irrespective of the organ type, with only two patients exhibiting variable responses across different organs. Furthermore, these responders had improved survival outcomes, including longer progression-free survival and overall survival, compared with non-responders. In terms of nivolumab monotherapy, the ORR was 21.3%. Nivo yielded OSORRs for 305 individual lesions: 13.5% in the liver, 25.3% in the lungs, 39.3% in the lymph nodes, and 18.4% at other sites. Conclusions: In contrast to lesions of patients who received Nivo, intrahepatic lesions of Ipi/Nivo-treated patients without prior ICI exposure exhibited favorable responses, comparable with treatment responses of extrahepatic lesions. Conversely, Ipi/Nivo-treated patients with prior ICI exposure had reduced organ-specific responses across all organs when compared with those without prior ICI exposure.