Background: Immunotherapy has garnered increasing attention in hepatocellular carcinoma (HCC) treatment. However, there remains a pressing need for effective immunological predictive biomarkers. In our previous study, utilizing data extracted from The Cancer Genome Atlas (TCGA) database, we identified a positive correlation between WDR4 expression levels in hepatocellular carcinoma and various clinical parameters, encompassing Stage, T-stage, pathological grade, AFP level, and vascular invasion. Additionally, higher WDR4 expression was linked to poorer prognosis. Leveraging The TIMER and GEPIA databases, we further elucidated a significant association between WDR4 expression levels and the extent of immune cell infiltration, particularly macrophages, B lymphocytes, and myeloid suppressor cells, in hepatocellular carcinoma. These findings propose the potential utility of WDR4 as a biomarker for immune infiltration in hepatocellular carcinoma. As noted in the trial NCT03867084, which hypothesized that adjuvant pembrolizumab might surpass placebo efficacy, there still exists a gap in identifying the specific population benefiting from adjuvant immunotherapy. Methods: Clinical and pathological data from patients who underwent single-agent immunotherapy for HCC were additionally collected from Hunan Provincial People's Hospital between January 1, 2019, and January 31, 2024. These patients participated in the clinical trial (NCT03867084) with informed consent. The relationship between WDR4 expression levels, clinical pathological data, and patient prognosis was assessed using the Kruskal-Wallis test and Kaplan-Meier survival curve analysis. Results: WDR4 displayed significant upregulation in HCC tissues compared to para-carcinoma tissues (P < 0.001) and exhibited robust diagnostic potential. WDR4 expression showed significant associations with various immune cells, including macrophages (r = 0.278, P < 0.001). Kaplan-Meier survival analysis indicated that patients with high WDR4 expression had shorter postoperative progression-free survival in the context of immunotherapy. Data from 37 patients who underwent postoperative single-agent immunotherapy for hepatocellular carcinoma (NCT03867084) revealed a significant correlation between WDR4 expression levels and Disease-Free Survival (DFS), with notable statistical significance (Log-rank P < 0.001). Conclusions: WDR4 demonstrates elevated expression levels within HCC tissues and is associated with immune infiltration, establishing it as a prognostic biomarker in HCC. Furthermore, the positive correlation observed between WDR4 and CD68 as well as PD-L1 underscores its potential as a guiding factor in immunotherapeutic approaches for HCC.