A key strategy in the elimination of hepatitis C virus (HCV) infection is the development of a safe and effective vaccine. A phase I/II randomized, double-blind, placebo-controlled trial assessed a prime–boost strategy with chimpanzee adenovirus 3 and modified vaccinia Ankara vectors encoding non-structural proteins of HCV genotype 1b. A total of 548 participants who were considered at risk of HCV infection on the basis of a history of recent injection drug use were randomly assigned to receive vaccine or placebo on days 0 and 56. No evidence of vaccine efficacy in preventing chronic HCV infection was observed as there was no statistically significant difference in the number of participants developing chronic HCV infection between groups. The HCV vaccine regimen did induce HCV-specific T-cell responses (in 78% of the vaccine group) and reduced the peak HCV RNA level in the vaccine group versus the placebo group. The number of serious adverse events were similar between groups.