Abstract: Aims/Background: There is a possibility that proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the inflammatory process of chronic hepatitis C. This study was undertaken to investigate the possible role of IL-6 in the pathophysiology of chronic hepatitis C. Methods: Serum IL-6 levels in 63 patients with chronic hepatitis C and in 26 normal controls were measured. Light and electron immunostaining studies to localize IL-6 protein as well as in situ hybridization to localize IL-6 messenger RNA were performed on 10 liver biopsy specimens. Results: Serum IL-6 levels were significantly (p<0.01) elevated in chronic hepatitis C compared to those in normal controls. Although no statistically significant correlation was found between serum IL-6 levels and hepatobiliary enzyme levels, a significant correlation (p<0.01) was found between serum IL-6 levels and category II of Knodell's histological activity index score. Non-parenchymal cells in hepatic sinusoids and the cells infiltrating enlarged fibrous portal tracts were definitely positive for IL-6 protein and mRNA by immunohistochemistry and in situ hybridization. In addition, immunoelectron microscopy revealed a weak and occasional positive reaction in the cytoplasm of hepatocytes. The majority of the positive cells in hepatic sinusoids showed CD68 immunoreactivity in consecutive sections indicating that these were Kupffer cells. Sinusoidal endothelial cells and hepatic stellate cells also exhibited a weak reaction. Conclusion: These results strongly suggest that Kupffer cells in liver parenchyma and macrophages infiltrating in portal tracts are the main producers of elevated IL-6 in serum. Moreover, there is a possibility that IL-6 produced by hepatocytes could also act as a regenerative stimulus to hepatocytes themselves in an autocrine fashion.