〔Abstract〕 Objective To investigate the expression of serum SPINK1 in hepatocellular carcinoma(HCC) patients, analyze the diagnostic efficacy of SPINK1 alone and combined with alpha fetoprotein(AFP) detection in HCC, and explore the value of SPINK1 in the short-term prognosis of HCC. Methods Serum was collected from patients in the HCC group(87 cases), patients in the chronic liver disease group(73 cases), and volunteers in the healthy control group(45 cases). Kruskal-Wallis H was used to compare the expression of SPINK1 among different groups, and analyze its relationship with Child-Pugh grades in HCC patients; the ROC curve was drawn and used to analyze the diagnostic efficacy of SPINK1, AFP and the combined detection for HCC. Risk factors for the Disease-free survival(DFS) of HCC were assessed by Kaplan-Meier and Cox regression analysis. Results Serum levels of SPINK1 and AFP were higher in the HCC group than those in the chronic liver disease and health control groups(χ2= 87.28,72.55, allP<0.01). Serum SPINK1 levels in chronic liver disease group were similar to those in healthy control group(P>0.05). The sensitivity of SPINK1 in the diagnosis of HCC was higher than that of AFP. There was no difference in AUC between the two biomarkers(P>0.05). The specificity and AUC of the combined were higher than that of any single one(P<0.05). The AUC of SPINK1 in the diagnosis of AFP-negative HCC was 81.70%(95%CI: 0.74-0.88), with the specificity and sensitivity as 71.18% and 95%(when the cut-off value was 1.75 ng/ml). Serum SPINK1 levels were different among HCC patients with different Child-Pugh grades(χ2=10.17,P<0.05). Short-time DFS of HCC in the high SPINK1 group was lower than that of the low SPINK1 group(P<0.01), Serum SPINK1 level was an independent risk factor for short-time DFS(HR=9.92, 95%CI: 2.82-34.87,P<0.01) in HCC patients. Conclusion Serum SPINK1 has high diagnostic value for HCC, especially in the diagnosis of AFP-negative HCC. Higher levels of SPINK1 have a high predictive value for short-time poor prognosis of HCC.