Factors associated with serum HCV antibody, HCV RNA level, and HCV genotype were assessed in 557 current and former drug users. Additional assays included HIV antibody, CD4+ lymphocyte counts, HIV viral loads, and hepatitis B markers. Seventy-five percent of subjects were anti-HCV positive, of whom 75% had detectable HCV RNA (median, 5.04 x 10(5) IU/mL; range, 1020-15.7 x 10(6)). On multivariate analysis HCV seropositivity was associated with history of drug injection, HIV seropositivity, and increased age and inversely with drug snorting. Among anti-HCV-positive persons, detectable HCV RNA was independently associated with HIV seropositivity, male gender, and history of injection and inversely associated with hepatitis B surface antigen positivity. Among persons with detectable HCV RNA, higher levels were independently associated with higher HIV viral load, increased age, and genotypes 2a and 2b. These findings demonstrate an association of HCV RNA level with HIV viral load, independent of the level of immunosuppression. However, a substantial degree of the person-to-person variability in the prevalence and level of detectable HCV RNA remains unexplained.