Purpose: Hepatocellular carcinoma (HCC) is a major malignancy and the common cause of cancer-related deaths. Surgical intervention provides superior long-term survival outcomes; however, perioperative mortality is a major concern for clinicians while making treatment decisions, especially for major hepatectomy. Scoring systems for predicting 90-day mortality in patients with HCC undergoing major hepatectomy are not available. Methods: This study used the Taiwan Cancer Registry Database that is linked to the National Health Insurance Research Database to analyze data of 60,250 patients with HCC who underwent major hepatectomy and determine risk factors to establish a novel predictive scoring system. By using the stepwise selection of the multivariate Cox proportional hazards model, we divided the patients with HCC undergoing major hepatectomy into four risk groups. Results: The Chang Gung-PohAi predictive scoring system exhibited significant differences in the 90-day mortality rate among the four risk groups (very low risk: 2.42%, low risk: 4.09%, intermittent risk: 17.1%, and high risk: 43.6%). Conclusion: The Chang Gung-PohAi predictive scoring system is a promising tool for predicting 90-day perioperative mortality in patients with HCC undergoing major hepatectomy.