Following major tissue injury, hyaluronic acid production increases as a rapid response survival mechanism. Increased hyaluronic acid production and turnover are often associated with increased hyaluronidase activity, the enzyme that degrades hyaluronic acid. We investigated whether hyaluronic acid and hyaluronidase can be used as non-invasive markers of acute disease activity in hepatitis C by studying 26 patients with acute hepatitis C, 89 with chronic hepatitis C and 32 healthy controls. Chronic hepatitis C subjects were classified into five subgroups according to the stage of liver flbrosis. Serum aspartate aminotransferase and alanine aminotransferase activities and hyaluronic acid levels were increased in hepatitis C patients compared with the controls. Serum hyaluronic acid elevation correlated with disease progression. Serum hyaluronidase activities were also increased in patients compared with the controls, but decreased with disease progression. We conclude that both hyaluronidase and hyaluronic acid may be useful as early non-invasive serum indicators of disease activity in acute hepatitis C.