Introduction: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths due to its often late stage diagnosis. Our previous study showed that dermcidin (DCD) may have the potential to be used as a serum biomarker for HCC for more timely diagnoses. Materials and Methods: In this study, we measured serum DCD and alpha-fetoprotein (AFP) levels in 87 HCC patients; 33 liver cirrhosis (LC); and 44 normal controls (NC), evaluated the relationship between DCD levels and clinicopathological parameters. Results: Serum DCD levels in HCC patients (27.03ng/mL) were significantly higher than in LC patients (24.78ng/mL, p<0.05), and NC subjects (18.98ng/mL, p<0.001). The optimum cutoff values were 25.75ng/mL for DCD and 9.86ng/mL for AFP. DCD had a greater area under the receiver operating characteristic curve (AUC) for differentiating HCC from the controls than AFP (AUC=0.769 vs. 0.729, respectively). Importantly, our cohort revealed that serum DCD levels were positively correlated with metastasis in HCC patients versus HCC patients without metastatic disease (32.31 vs. 23.95, p<0.001). Western blot results showed that DCD expression was significantly upregulated in seven tumor tissues compared with the noncancerous adjacent tissues. Immunohistochemistry performed in four paired samples confirmed the upregulation of DCD expression in the tumor tissues. Conclusions: Our results showed that serum DCD levels were significantly increased in HCC patients and in cancerous tissue. DCD could potentially be used as a biomarker for the diagnosis of HCC.