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Abstract Background Prothrombin induced by vitamin K absence‐II (PIVKA‐II) and Alpha‐fetoprotein (AFP) have been widely used as diagnostic markers in hepatocellular carcinoma (HCC), but the prognostic values of the two serum markers and their clinical usefulness in patient selection for different surgical approaches remain largely unclear. Methods HCC patients received surgical treatment between 2015 and 2019 were included. Patients were divided into four statuses according to the serum PIVKA‐II and AFP secretion status: PIVKA‐II (−) AFP (−) (status 1); PIVKA‐II (+) AFP (−) (status 2); PIVKA‐II (−) AFP (+) (status 3); PIVKA‐II (+) AFP (+) (status 4). Kaplan–Meier analyses were conducted to compare the survivals of the four groups and the HCC patients received different surgical interventions; time‐dependent AUC curves were introduced to evaluate the prognostic value of the PIV‐AFP status; Cox regression model was used to identify prognostic indexes for overall survival (OS) and recurrence‐free survival (RFS). Results A total of 518 patients were included. Patients with PIVKA‐II (+) and APF (+) presented significantly decreased OS and RFS comparing to the other statuses. The areas under ROC curves of PIV‐AFP status in predicting OS and RFS were superior to the PIVKA‐II or the AFP alone. The HCC patients in early stages with PIVKA‐II (+) and APF (+) had worse RFS when received laparoscopic hepatectomy than those who received open hepatectomy, whereas there was no difference in other secretion statuses. The PIVKA‐II (+) and AFP (+) secretion status was an independent risk factor for OS, RFS. Conclusions The PIV‐AFP secretion status is of favorable clinical utility in predicting the OS and RFS of the HCC patients; extra caution is needed when applicated the laparoscopic approach in the HCC patients with PIVKA‐II (+) and AFP (+).