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The purpose of this study was to detect the expression of high-temperature requirement A2 (HtrA2) and its diagnostic value in the patients with hepatocellular carcinoma (HCC).The relative serum HtrA2 expression at mRNA and protein level was severally detected by quantitative real-time polymerase chain reaction and western blot analysis in 198 HCC patients and 48 healthy controls. And its association with clinicopathological features was analyzed by chi-square test. The diagnostic value of HtrA2 expression was estimated by establishing a receiver operating characteristic (ROC) curve.Serum HtrA2 was significantly higher in patients with HCC than that in healthy controls both at mRNA and protein levels (P < .05 for both). In addition, the high HtrA2 expression was associated with large tumor size and advanced clinical stage. Furthermore, the value of the area under the ROC curve was 0.808 corresponding with a sensitivity of 65.2% and a specificity of 89.6%, revealed that HtrA2 might be a diagnostic biomarker in HCC.HtrA2 is upregulated and considered to be a potential biomarker for the diagnosis of patients with HCC.