Objective To investigate the prognostic significance of preoperative serum alpha-fetoprotein isoform L3 (AFP-L3) and protein induced by vitamin K absence or antagonist-II (PIVKA-Ⅱ) in patients with hepatocellular carcinoma (HCC) undergoing curative resection.Methods Clinical data from 207 patients with HCC who underwent curative resection at the Qinhuai Medical Zone, General Hospital of Eastern Theater Command between January 2021 and December 2023 were retrospectively analyzed. Patients were categorized according to optimal cutoff values of preoperative AFP-L3 and PIVKA-Ⅱ levels, and clinicopathological characteristics were compared across groups. Based on postoperative follow-up outcomes, patients were further classified into favorable- and poor-prognosis groups, and differences in preoperative biomarker levels were assessed. Cox proportional hazards regression was applied to identify factors associated with overall survival (OS) and to determine independent adverse prognostic indicators. Survival outcomes were evaluated using Kaplan-Meier analysis, with intergroup comparisons performed by the log-rank test.Results Compared with the AFP-L3 high-level group, the AFP-L3 low-level group showed higher proportions of tumors < 5 cm in diameter, solitary tumors, and China Liver Cancer (CNLC) stage Ⅰ/Ⅱ disease, with a lower incidence of microvascular invasion (all P < 0.05). The PIVKA-Ⅱ low-level group had higher proportions of tumors < 5 cm and CNLC stage Ⅰ/Ⅱ disease and a lower rate of microvascular invasion than the PIVKA-Ⅱ high-level group (all P < 0.05). Preoperative AFP-L3 and PIVKA-Ⅱ levels were higher in the poor-prognosis group than in the favorable-prognosis group (P < 0.05). Microvascular invasion [H^R = 2.003 (95% CI: 1.230, 3.260) ], CNLC stage Ⅲa [H^R = 2.126 (95% CI: 1.241, 3.643) ], AFP-L3 > 12% [H^R = 2.150 (95% CI: 1.047, 4.417) ], and PIVKA-Ⅱ > 221 mAU/mL [H^R = 2.120 (95% CI: 1.195, 3.761) ] were identified as independent adverse prognostic factors for OS after curative resection (all P < 0.05). The cumulative survival rate was lower in the high PIVKA-Ⅱ group than in the low PIVKA-Ⅱ group (P < 0.05), and lower in the high AFP-L3 group than in the low AFP-L3 group (P < 0.05).Conclusion Preoperative serum AFP-L3 and PIVKA-Ⅱ levels are closely associated with survival outcomes after curative resection for HCC. Combined detection of these biomarkers can improve the prediction of postoperative recurrence and adverse outcomes, providing a reliable basis for preoperative risk stratification and individualized treatment strategies.