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INTRODUCTION AND AIMS: While people who inject drugs are at high risk of hepatitis C virus (HCV) infection and will be the target population for future HCV vaccine trials, little is known about clinical trial literacy (CTL) in this group. We assessed the impact of a brief intervention (BI) designed to improve HCV vaccine CTL among people who inject drugs in Sydney, Australia. DESIGN AND METHODS: People who inject drugs enrolled in a community-based prospective observational study between November 2008 and September 2010 (n = 102) completed a CTL assessment followed immediately by the BI. Post-test assessment was conducted at 24 weeks. RESULTS: The median age of the sample was 27 years, 73% were male and 60% had 10 or less years of schooling. The median time since first injection was 5 years and 20% reported daily or more frequent injecting. The mean number of correct responses increased from 5.3 to 6.3/10 (t = 4.2; 101df, P < 0.001) 24 weeks post-intervention. Statistically significant differences were observed for three knowledge items with higher proportions of participants correctly answering questions related to randomisation (P = 0.002), blinding (P = 0.005) and vaccine-induced seropositivity (P = 0.003) post-intervention. DISCUSSION AND CONCLUSIONS: A significant increase in HCV vaccine CTL was observed, suggesting that new and relatively novel concepts can be learned and recalled in this group. These findings support the feasibility of future trials among this population.