In patients infected with the hepatitis C virus (HCV), 20% to 30% will progress to cirrhosis in over two to three decades. Viral and host factors that are important in the clinical and histologic progression of HCV infection are not entirely certain. It has been suggested that liver disease is worse in alcoholics infected with HCV. In the present retrospective study, we examined the effect of moderate alcohol intake on the histologic and clinical progression of HCV infection and assessed whether other variables such as gender, length of exposure, mode of exposure, HCV RNA levels, and ferritin levels also independently impacted disease progression. Liver biopsies were analyzed for the degree of fibrosis, presence of cirrhosis, and histologic activity by using the Histologic Activity Index of Knodell. Patients were divided into two groups based on whether their alcohol intake was significant or not significant. Significant alcohol intake was defined as G40 g alcohol/day in women and G60 g of alcohol/day in men for G5 years. Groups were further divided based on the decades of exposure to HCV. There was no difference in the age or length of exposure to HCV in the alcohol and the alcoholfree group. HCV RNA serum levels, ferritin levels, and viral genotypes were similar in both groups. There was a two-to threefold greater risk of liver cirrhosis and decompensated liver disease in the alcohol group. Also, the rate to which subjects developed cirrhosis was faster in the alcohol group with 58% being cirrhotic by the second decade as opposed to 10% being cirrhotic in the nonalcohol group by the second decade. The histologic and clinical acceleration of liver disease was independent of the mode of exposure or sex. In summary, alcohol intake is an independent risk factor in the clinical and histologic progression of HCV infection. (HEPATOLOGY 1998;28:805-809.)In the United States 3 to 4 million people are infected with HCV. HCV infection is an indolent disease with patients rarely having clinical symptoms until cirrhosis develops. Ten to thirty percent of patients infected with HCV will develop cirrhosis over a 20 to 30 year period, and 1% to 5% will develop hepatocellular carcinoma. [1][2][3][4] Host and viral factors that are important in enhancing the progression to cirrhosis are not entirely clear. 5 Proposed contributory factors include viral genotype, circulating viral load, duration of infection, mode of infection, iron load, gender, and alcohol consumption. [1][2][3][4][5] It is recognized that 5% to 25% of chronic alcoholics with liver disease have a positive HCV antibody test. 6-12 Also, a number of studies have suggested that patients with alcoholic liver disease who are infected with the HCV have more impaired biochemical function and a greater chance of developing cirrhosis. [6][7][8][9][10][11][12] Alcohol intake has also been implicated as an independent risk factor in the progression of HCV, 13 although its overall effect on both the histologic and clinical progression of liver disease in patients chronicall...