Des-gamma-carboxy prothrombin (DCP), also known as protein induced by vitamin K absence or antagonist II absence (PIVKA-II), has been considered as a useful serum tumor marker for hepatocellular carcinoma (HCC). However, the underlying mechanism causing the elevation of serum DCP levels in HCC patients remains unclear. This study was undertaken to identify the relationship between serum DCP levels and the expression of DCP in cancer and surrounding non-cancer liver tissues of HCC patients. Serum and tissue samples prepared from 92 patients with a single HCC nodule were subjected to clinicopathological study by measuring serum DCP levels and performing immunohistochemical staining for tissue DCP. Serum DCP levels correlated significantly with clinicopathological factors such as hepatitis markers, tumor differentiation, vascular invasion, intrahepatic metastasis, TNM stage, tumor size, tumor recurrence, and patient survival. DCP immunohistochemical staining was positive in cancer tissues for 68 (68/92, 73.9%) patients and in non-cancer tissues surrounding tumors for 24 (24/92, 26.1%) patients. There was no apparent correlation between serum DCP values and the expression of DCP in HCC tissues; however, there was a significant correlation between serum DCP levels and the expression of DCP in non-HCC tissues (p=0.0398). In conclusion, our results suggest that the origin of elevated serum DCP may lie not only in HCC tissue but also in non-cancer tissues. The HCC lesion itself appears to influence the production of DCP in surrounding non-cancer tissues.