Background: High alpha-fetoprotein (AFP) expressions (>400 ng/mL) are associated with poor oncological characteristics for hepatocellular carcinoma (HCC). However, prognosis after liver resection for high-AFP HCC is poorly studied. To investigate long-term recurrence and survival after hepatectomy for high-AFP HCC, and to identify the predictive value of postoperative incomplete biomarker response (IBR) on overall survival (OS) and recurrence-free survival (RFS). Methods: Patients undergoing curative resection for high-AFP HCC were analyzed. According to the decline magnitude of serum AFP as measured at first follow-up (4 similar to 6 weeks after surgery), all patients were divided into the complete biomarker response (CBR) and IBR groups. Characteristics, recurrence, and survival rates were compared. Univariate and Multivariate Cox-regression analyses were performed to identify independent predictors associated with poorer OS and RFS after liver resection for high-AFP HCC. Results: Among 549 patients, the overall and early recurrence rates in patients with IBR were significantly higher than patients with CBR (97.8%vs.56.4%, and 92.5%vs.33.3%, both P<0.001). On multivariate analysis, postoperative IBR was the strongest risk factor with the highest hazard ratio in predicting poor OS (HR 2.97; 95% CI 2.49 similar to 3.45; P<0.001) and RFS (HR 4.29; 95% CI 3.31 similar to 5.55; P<0.001). Conclusion: Postoperative biomarker response of serum AFP can be used in predicting recurrence and survival for high-AFP HCC patients. Once postoperative IBR was identified at first follow-up, subsequent enhanced recurrence surveillance and available treatments against recurrence should actively be considered.