Between May 1996 and June 1998, 210 members of a cohort of 1,667 hepatitis C virus (HCV)-infected injection drug users (IDUs) were selected for liver biopsy procedure after stratification based on 2 consecutive serum alanine transaminase (ALT) levels. Liver histology, which could be fully evaluated for 207 subjects, was classified by using the modified Ishak scores. At the time of biopsy, the median age of subjects was 41.3 years and the median estimated duration of HCV infection was 20.7 years; 94% were African American; 78% men; 31% were human immunodeficiency virus (HIV) seropositive; and 76% had HCV genotype 1a or 1b. Total modified histologic activity index (MHAI) scores ranged from 0 to 9, and 26.6% had a total MHAI score of 5 or greater. Persons with a total MHAI score of 5 or greater were more likely to be HIV infected (P =.04). Higher fibrosis, indicated by Ishak modified fibrosis scores of 3 to 6, was present in 10.1% of subjects and was found more often in those older than 46 years of age (the highest quartile) (P <.01). Both fibrosis scores of 3 or greater and total scores of 5 or greater were associated with elevated ALT, aspartate transaminase (AST), and gamma-glutamyl transpeptidase (GGT) levels (P <.01). When serial values were considered, the results of liver enzyme testing could reduce the probability of an IDU having a fibrosis score of 3 or greater from 10% to 3%. In conclusion, these data indicate that severe liver disease is uncommon in this urban, HCV-infected IDU cohort, especially in younger persons and those with repeatedly normal liver enzymes.