We studied trace metals (copper, iron, zinc) in patients with hepatocellular carcinoma (HCC) with special reference to carcinogenesis. 1. High signal intensity on T1-weighted images in magnetic resonance imaging, suggestive of HCC, was due to excessive accumulation of copper within the tumor. 2. Hepatic copper content increased with progression of hepatic fibrosis (p<0.05). However, hepatic iron and zinc contents did not show a significant difference between grades of fibrosis. 3. In patients with grade F3 or F4 fibrosis, copper content in the liver parenchyma was higher in the presence of HCC than in its absence (p<0.05). Multiple regression analysis showed that the only factor significantly associated with the coexistence of HCC in HCV-positive patients with chronic liver disease was the copper level in the liver parenchyma. Thus, hepatic copper overload may contribute to the development of HCC in HCV-positive patients with chronic hepatitis or cirrhosis. 4. Accumulation of copper in small HCC, in which copper was present as Cu-MT or Zn, Cu-MT, was greater than that in the surrounding liver parenchyma. 5. Content of 8-hydroxydeoxyguanosine was higher in HCC and its surrounding liver parenchyma than normal liver parenchyma (p<0.05). Thus, copper accumulation and the presence of MT in the liver may be related to carcinogenesis of HCC.