Background-Heavy alcohol use, hepatitis C and illicit drug use each have been shown to have negative impacts on health-related quality of life (HRQL). To date, considerations of HRQL have not played a prominent role in the design and measurement of intervention strategies for out-oftreatment at-risk populations.Methods-Data were collected from out-of-treatment IDUs recruited through street outreach in North Carolina. Multiple linear regression analyses were used to examine the independent effects of HCV status, harmful drinking (AUDIT), and illicit drug use on HRQL (SF-36).Results-Fifty-one percent of 619 study participants tested HCV-positive; 57% met criteria for harmful or hazardous drinking and 63% reported daily use of hard drugs. HRQL scores for this population were significantly lower than those of the general population. Multiple linear regression analyses demonstrated that harmful levels of alcohol consumption and use of methamphetamine in the past month had the strongest associations with reduced HRQL.Conclusions-Given the high rates of HCV in most IDU communities, new harm reduction approaches are needed for these populations which focus beyond prevention to the functioning and well-being of those already infected. In particular, reducing heavy alcohol use in addition to slowing HCV progression shows promise for improving HRQL.