<p>Post-hepatectomy liver failure (PHLF) remains a serious complication following liver resection, yet early prediction is an unmet clinical need. This prospective study enrolled 151 patients at elevated risk of PHLF (major hepatectomy, thrombocytopenia, or hyperbilirubinemia) and evaluated serum antithrombin III (ATIII) activity, measured preoperatively and on postoperative days (PODs) 1, 2, 3, and 5, as an early predictive marker. PHLF, diagnosed according to the International Study Group of Liver Surgery criteria, occurred in 35 patients (23.2%). ATIII activity was evaluated as raw values and as the percentage change from the preoperative baseline. Raw ATIII activity was significantly lower in the PHLF group at all time points (<i>P</i> &lt; 0.001). The POD 3 ATIII decrease was significantly greater in the PHLF group (36% vs. 29%, <i>P</i> = 0.041). Multivariable logistic regression identified ATIII change from baseline ≥ 30% at POD 3 (odds ratio 3.04, <i>P</i> = 0.021), ALBI grade B (OR 2.77, <i>P</i> = 0.031), and ICG R-15 ≥ 15% (OR 3.50, <i>P</i> = 0.034) as independent risk factors for PHLF. The multivariable model demonstrated acceptable discriminative performance (apparent AUC 0.750; bootstrap-corrected AUC 0.730). These findings suggest that early postoperative decline in ATIII activity could serve as an early biomarker for identifying patients at increased risk of PHLF, potentially enabling timely intervention.</p>