The recurrence rate of hepatocellular carcinoma (HCC) remains high and multinodular HCC is a well-defined high-risk factor. This trial is to evaluate the safety and efficacy of cadonilimab plus HAIC as a neoadjuvant management for the resectable multinodular HCC with CNLC stage Ⅰb/Ⅱa. In this ongoing single-center, phase 2, open label, prospective cohort clinical trial, eligible patients (pts) were randomly assigned (1:1:1) to 3 arms and receive neoadjuvant therapy: (A) 2 cycles of cadonilimab (6mg/kg Q2W); (B) once HAIC with FOLFOX regimen followed by 2 cycles of cadonilimab; (C) once FOLFOX-HAIC. Pts receive scheduled surgery on day 21-28 and adjuvant HAIC one month after surgery. Primary endpoints were major pathologic response (MPR defined as ≤50% residual living tumor) and 1-year RFS rate. Secondary endpoints included ORR, DCR and TRAEs. From January 4 to August 20, 2023, 18 pts were enrolled and 16 pts have received scheming hepatectomy (5 pts in Arm A, 9 pts in Arm B, 2 pt in Arm C). Remarkably, almost all (8/9) pts in Arm B achieved MPR and some pts demonstrated focal heterogeneity—one lesion achieved pathologic complete response, while another got non-/partial response. No obvious tumor necrosis in Arm A and C, but the inflammatory infiltrating and fibrosis area seemed to increase in some HCC lesions. 3 pts in Arm B (3/9) achieved PR and DCR was 100% per RECIST 1.1. The most common TRAEs in Arm B and C were increased ALT, AST (Grade 1-3) and bilirubin (Grade 1), which mainly resulted from HAIC and can be improved by routine liver protection treatment. Main TRAEs observed in Arm A was increased AST (Grade 3). Two pts in Arm A and B delayed scheduled surgery for 3 weeks due to increased ALT/AST. One pt experienced postoperative controllable pneumonia which may relate to novel coronavirus (2019-nCoV) and cadonilimab. One pt experienced postoperative severe but curable bacterial hepatic abscess related to bilioenteric anastomosis and diabetes mellitus. This study preliminarily demonstrated that neoadjuvant cadonilimab plus FOLFOX-HAIC had a promising antitumor activity and a manageable safety for the resectable multinodular HCC.