Most people who inject drugs (PWID) are infected with hepatitis C virus (HCV), and PWID have the highest risk of HCV infection of any risk group. The incidence of HCV infection is 5%–25% per year, demonstrating continued need for HCV infection prevention in PWID. Existing data in chimpanzees and PWID suggest that protective immunity against persistent HCV infection is achievable. Due to the high incidence of infection, PWID are both the most likely to benefit from a vaccine and a population in which vaccine efficacy could be tested. Challenges to testing a vaccine in PWID are significant. However, the first HCV vaccine trial in at-risk HCV-uninfected PWID was initiated in 2012. The results will likely guide future vaccine development and strategies for vaccination of this and other high-risk populations.