Combination of targeted therapy and immune checkpoint inhibitors (ICIs) is a leading approach in the treatment of advanced hepatocellular carcinoma (HCC). However, an increased incidence of skin rashes poses a clinical challenge. Understanding the acute cutaneous adverse drug reactions (CADRs) during the early stage of the combination treatment is crucial.To investigate the clinical characteristics of acute CADRs in HCC patients undergoing combined targeted agents and ICIs and identify potential risk factors contributing to the development of severe CADRs phenotypes.A retrospective analysis of 33 HCC patients with acute CADRs following combination therapy was conducted. Patients were categorized into maculopapular eruption (MPE) group and atypical targetoid eruption (ATE) group based on the rash phenotypes. Clinical characteristics were compared between the subgroups, and the administration pattern of the combination therapy was analyzed.16 MPE cases and 17 ATE cases were identified. No other types of acute skin eruptions were documented. Patients with ATE developed rashes with a shorter time latency, experienced more systemic symptoms, showed higher severity grades, had longer disease courses, and demonstrated a lower rate of successful rechallenge compared to patients with MPE. The ATE group displayed a significantly higher percentage receiving full-dose targeted agents and a shorter interval between targeted agents and ICIs upon initiation of combination therapy.In HCC patients receiving combined regimens, atypical targetoid rashes indicate a more severe CADR. Full-dose targeted agents and shorter intervals between targeted agents and ICIs may contribute to the more severe CADR phenotype.