BACKGROUND: Immune checkpoint inhibitors have proven efficacy against hepatitis B-virus positive hepatocellular. However, Immunotherapy-related adverse reactions are still a major challenge faced by tumor immunotherapy, so it is urgent to establish new methods to effectively predict immunotherapy-related adverse reactions. OBJECTIVE: Multi-machine learning model were constructed to screen the risk factors for irAEs in ICIs for the treatment of HBV-related hepatocellular and build a prediction model for the occurrence of clinical IRAEs. METHODS: Data from 274 hepatitis B virus positive tumor patients who received PD-1 or/and CTLA4 inhibitor treatment and had immune cell detection results were collected from Henan Cancer Hospital for retrospective analysis. Models were established using Lasso, RSF (RandomForest), and xgBoost, with ten-fold cross-validation and resampling methods used to ensure model reliability. The impact of influencing factors on irAEs (immune-related adverse events) was validated using Decision Curve Analysis (DCA). Both uni/multivariable analysis were accomplished by Chi-square/Fisher's exact tests. The accuracy of the model is verified in the DCA curve. RESULTS: A total of 274 HBV-related liver cancer patients were enrolled in the study. Predictive models were constructed using three machine learning algorithms to analyze and statistically evaluate clinical characteristics, including immune cell data. The accuracy of the Lasso regression model was 0.864, XGBoost achieved 0.903, and RandomForest reached 0.961. Resampling internal validation revealed that RandomForest had the highest recall rate (AUC = 0.892). Based on machine learning-selected indicators, antiviral therapy and The HBV DNA copy number showed a significant correlation with both the occurrence and severity of irAEs. Antiviral therapy notably reduced the incidence of IRAEs and may modulate these events through regulation of B cells. The DCA model also demonstrated strong predictive performance. Effective control of viral load through antiviral therapy significantly mitigates the occurrence of irAEs. CONCLUSION: ICIs show therapeutic potential in the treatment of HBV-HCC. Following antiviral therapy, the incidence of severe irAEs decreases. Even in cases where viral load control is incomplete, continuous antiviral treatment can still mitigate the occurrence of irAEs.