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Background Advanced-stage hepatocellular carcinoma (HCC) with high tumour burden and portal vein tumour thrombus (PVTT) is usually associated with poor survival outcomes. Rapid tumour control usually benefits long-term outcomes, which could be hardly achieved by solely systematic targeted and immunotherapy in current guidelines. Hepatic arterial infusion chemotherapy (HAIC) is reported as an effective intervention for rapid decrease of tumour burden. In order to determine the role of HAIC in the comprehensive treatments, a target trial emulation study is conducted to compare the effectiveness and safety of HAIC in combination with lenvatinib and programmed death receptor-1 (PD-1) inhibitors (H+L+P) to that of lenvatinib and PD-1 inhibitors (L+P) in patients with advanced HCC exhibiting high tumour burden and PVTT.Methods and analysis This target trial emulation study will be conducted at nationwide, multicentre CHANCE registries in China. We aim to include at least 228 patients with advanced-stage HCC with high tumour burden (up-to-seven criteria out) and PVTT who received L+P with or without HAIC as the first-line treatment between January 2021 and December 2023. The study design adheres to the framework of target trial emulation. To mitigate biases, a stabilised inverse probability of treatment weighting will be conducted. Overall survival is defined as the primary endpoint. Secondary endpoints consist of progression-free survival, objective response rate and adverse events.Ethics and dissemination Our study was approved by the Medical Research Ethics Committee of the First Hospital of China Medical University, and the study protocol was also approved by the institutional review boards of participating centres. The ethics committee waived informed consent because the study was retrospective. The findings of this study will be submitted for publication in peer-reviewed journals and will also be shared at multiple conferences on interventional radiology and oncology, ranging from local to international.Trial registration number NCT06631326.