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Background With the advent of immune checkpoint inhibitor-based combination therapy, treatment sequencing for advanced hepatocellular carcinoma (HCC) has become increasingly complex. The Barcelona Clinic Liver Cancer (BCLC) 2026 recommendations emphasize individualized decision-making. Purpose To compare clinical outcomes of hepatic arterial infusion chemotherapy (HAIC) and tyrosine kinase inhibitors (TKIs) in patients with advanced HCC after atezolizumab-bevacizumab (AB) failure, within the BCLC 2026 treatment paradigm. Materials and Methods This multicenter retrospective study included patients who received AB and subsequently received either HAIC or a TKI between March 2022 and August 2025. HAIC used a cisplatin-fluorouracil regimen, and TKIs were given at standard doses. Tumor response and progression-free survival (PFS) were assessed using contrast-enhanced multiphase CT or liver MRI according to routine clinical practice. Imaging was reviewed by radiologists blinded to treatment allocation. Inverse probability of treatment weighting (IPTW) was applied for age, sex, Eastern Cooperative Oncology Group performance status, Child-Pugh class, portal vein tumor thrombosis, and tumor burden based on the up-to-seven criteria. Results This study included 90 patients (mean age, 62 years ± 10.9 [SD]; 73 men; HAIC group, n = 51; TKI group, n = 39). Baseline tumor burden was higher in the HAIC group than in the TKI group (percentage of patients with tumors beyond the up-to-seven criteria: 88% [45 of 51] vs 64% [25 of 39]; P = .01). In unweighted analyses, median overall survival (OS) was similar between the HAIC and TKI groups (10.4 vs 6.4 months; P = .62), whereas PFS favored HAIC over TKIs (median, 5.3 vs 3.6 months; P = .008). Objective response rate and disease control rate were higher with HAIC than with TKIs (objective response rate: 35% [18 of 51] vs 5% [two of 39], P = .002; disease control rate: 67% [34 of 51] vs 26% [10 of 39], P < .001). After IPTW, HAIC remained associated with longer PFS than TKIs (median, 7.1 vs 3.4 months; P < .001), and OS remained similar between groups (median, 10.5 vs 6.3 months; P = .32). Conclusion In patients with advanced HCC, after AB failure, second-line HAIC yielded higher response rates and longer PFS than TKIs. © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Deyirmendjian and Tang in this issue.