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Injection drug users (IDUs) are at risk of acquiring hepatitis C virus (HCV) infection. We have identified a cohort of long-term IDUs who remain uninfected by HCV despite high-risk behavior. We have categorized these subjects as “exposed uninfected” and have sought immunological correlates with this apparent resistance.We studied 40 exposed uninfected subjects testing negative for both HCV antibody and HCV RNA. Details of injection behavior were ascertained by questionnaire. In vitro interferon (IFN)-γ production by T cells in response to HCV proteins (core, E1, NS3, NS4, and NS5) was quantified by enzyme-linked immunospot assay, and findings were compared with those in 21 healthy control subjects.All exposed uninfected subjects reported sharing needles or other injection paraphernalia on multiple occasions. The mean duration of injecting was 9.3 years (range, 0.5-26 years), with a median estimated number of injection episodes of 8760. IFN-γ production in response to HCV proteins was found in 23 (58%) of 40 exposed uninfected subjects versus 4 (19%) of 21 control subjects (P=.004), with 14 exposed uninfected subjects responding to multiple antigens, compared with none of the control subjects (P=.001).The majority of long-term IDUs who remain uninfected by HCV despite their high-risk behavior have HCV-specific T cell responses. These responses were frequently found for multiple HCV proteins, making cross-reactivity to other homologous antigens unlikely. These responses may represent an immunological footprint of HCV exposure that has not resulted in viremia or HCV antibody seroconversion. The potential role played by these responses in protection from HCV infection is of clinical importance.