Objective To study the effect of alpha fetoprotein-tumor burden score (ATS) on the long-term prognosis of hepatocellular carcinoma (HCC) after resection. MethodsThe data of 2 907 patients with HCC who underwent first hepatectomy from West China Hospital of Sichuan University, West China Ziyang Hospital/Ziyang Central Hospital, The First People’s Hospital of Neijiang, West China Yibin Hospital/The Second People’s Hospital of Yibin between 2015 and 2022, were retrospectively analyzed. The X-tile software was used to calculate the optimal truncation of the ATS score. Cox proportional hazard regression model was used to explore risk factors affecting postoperative recurrence-free survival (RFS) and overall survival (OS) in HCC patients, respectively. ResultsAll patients were followed-up with a median of 37 months, 1 364 cases (46.9%, the recurrence time was 1–89 months after surgery) of them experienced recurrence and 841 cases (29.1%) died (the death time was 1–88 months after surgery). The 1-, 2- and 3-year OS rates were 89.3%, 81.4% and 75.9%, respectively. The 1-, 2- and 3-year RFS rates were 76.0%, 64.3% and 57.2%, respectively. The 5-year RFS rate of HCC patients with low-, medium-, and high-ATS scores were 56.4%, 45.0% and 27.2%, respectively, and patients with low ATS score had better RFS (χ2=264.747, P<0.001). The 5-year OS rate of HCC patients with low-, medium-, and high- ATS scores were 78.0%, 59.8% and 38.8%, respectively, and patients with low-ATS score had better OS (χ2=372.685, P<0.001). Multivariate Cox proportional hazard regression model suggested that, in condition of adjusting gender, age, liver function, microvascular invasion, tumor differentiation, and BCLC stage, medium-ATS score [RR=1.375, 95%CI (1.209, 1.564), P=0.005] and high-ATS score [RR=2.048, 95%CI (1.764, 2.377), P<0.001] were risk factors for postoperative RFS; the medium-ATS score [RR=1.779, 95%CI (1.499, 2.112), P<0.001] and high ATS score [RR=2.676, 95%CI (2.211, 3.239), P<0.001] were also risk factors affecting postoperative OS. ConclusionATS score can predict the prognosis of HCC patients after resection, patients with high ATS scores had a higher incidence of postoperative recurrence and mortality.