BACKGROUND AND OBJECTIVES: The importance of sexual transmission of hepatitis C virus (HCV) infection is unclear. We attempted to define its role in women with or at risk for HIV infection. GOAL OF THIS STUDY: To ascertain if high-risk sexual behavior was independently associated with HCV infection. STUDY DESIGN: Risk factors were assessed cross-sectionally in Chicago women newly enrolled in the Women's Interagency HIV Study. Women who had (n = 243) or were at risk for HIV infection (n = 53) were tested for HCV antibodies (Ab). RESULTS: Of 296 women, 123 (42%) were HCV Ab positive; prevalence was 90% in women who injected drugs (IDU) compared with 12% in noninjectors (odds ratio [OR], 64.0, 95% confidence interval [CI], 29.9 to 137.0). A multivariate model showed associations with IDU (OR, 110.3, 95% CI, 33.3 to 365.8), prior gonorrhea (OR, 3.6, 95% CI, 1.4 to 8.9), and sex with a male IDU (OR, 2.7, 95% CI, 1.1 to 7.0). CONCLUSION: Injection drug use is the strongest predictor of HCV infection, but sexual risk factors are also independently associated.