OBJECTIVE: To describe the prevalence of hepatitis C virus (HCV) infection in a sample of homeless and impoverished adults and examine risk factors for HCV infection in the overall sample and as a function of injection drug use. DESIGN: Assays were conducted on stored sera. Sociodemographic characteristics and risky sexual activity were measured by content-specific items. Substance use was measured by a structured questionnaire. HCV antibodies were tested by enzyme-linked immunosorbent assay; a confirmatory level was defined by recombinant immunoblot assay. SETTINGS: Shelters ( N = 36) and outdoor locations in Los Angeles. PARTICIPANTS: Eight hundred eighty-four homeless women and/or partners or friends. RESULTS: Among this sample of 884 homeless and impoverished adults, 22% were found to be HCV infected. Lifetime injection drug users (IDUs) (cocaine, crack, and methamphetamine) and recent daily users of crack were more likely than nonusers or less-frequent users of these drugs to be HCV-infected. Similar results were found for those who had been hospitalized for a mental health problem. Among non–injection drug users and persons in the total sample, those who reported lifetime alcohol abuse were more likely than those who did not to be HCV infected. Controlling for sociodemographic characteristics, multiple logistic regression analyses revealed IDUs have over 25 times greater odds of having HCV infection than non-IDUs. HCV infection was also predicted by older age, having started living on one's own before the age of 18, and recent chronic alcohol use. Males and recent crack users had about one and a half times greater odds of HCV infection when compared to females and non–chronic crack users. CONCLUSIONS: Targeted outreach for homeless women and their partners, including HCV testing coupled with referrals to HCV and substance abuse treatments, may be helpful.