Purpose. To assess the impact of illicit drug use and chronic hepatitis C virus (HCV) on health-related quality of life (HRQoL) in women with HIV or at risk for HIV infection. Methods. Cross-sectional analysis of data from the Women’s Interagency Health Study (WIHS) of women with HIV (n = 2508) and at high risk of HIV infection (n = 889) in the US. A Short-Form-6D (SF-6D) HRQoL measure derived from the Medical Outcomes Study–HIV (MOS-HIV) questionnaire, HIV infection status, CD4 cell count (a measure of immune status), antiretroviral treatment, current illicit drug use (heroin and/or cocaine), and HCV status were assessed at a recent study visit. We developed multivariate linear regression models adjusting for age, race/ethnicity, education, and testing for interactions. Results. HIV-infected women with ≤200 CD4 cells/µL had lower mean HRQoL scores (0.69) than either HIV-infected women with >200 CD4 cells/µL (0.78) or HIV-uninfected women (0.80) (P < 0.01). In multivariate analysis, illicit drug use, chronic HCV, and low CD4 count were independently associated with lower HRQoL. There was a differential effect of HCV and illicit drug use for HIV-infected women depending on CD4 cell count: HIV-infected women with >200 CD4 cells/µL had a significantly greater reduction in HRQoL associated with illicit drug use (–0.063) and chronic HCV (–0.036) than women with ≤200 CD4 cells/µL (–0.017, –0.005 respectively). Conclusions. Poorly controlled HIV, illicit drug use, and chronic HCV are associated with lower HRQoL. Illicit drug use and chronic HCV have greater HRQoL impacts for HIV-infected women with well-controlled HIV versus those with poorly controlled HIV, which may affect clinical and policy priorities.