Efficacy trials of preventive hepatitis C virus (HCV) vaccine candidates raise challenging scientific and ethical issues. Based on data from the first 3years of a community-based prospective observational study - the Hepatitis C Incidence and Transmission Study-community (HITS-c) - this paper examines the feasibility of conducting trials of candidate HCV vaccines with people who inject drugs (PWID) in Sydney, Australia. Of the 166 PWID confirmed HCV antibody negative and eligible for enrolment, 156 (94%) completed baseline procedures. Retention was high, with 89% of participants retained at 48weeks and 76% of participants completing at least 75% of study visits within 2weeks of schedule. The rate of primary HCV infection was 7.9/100py (95% CI 4.9, 12.7). Of the 17 incident cases, 16 completed at least one follow-up assessment and 12 (75%) had evidence of chronic viraemia with progression to chronic HCV infection estimated to be 6/100py. Power calculations suggest a chronic HCV infection rate of at least 12/100py (primary HCV infection rate 16/100py) will be required for stand-alone trials of highly efficacious candidates designed to prevent chronic infection. However, elevated primary HCV infection was observed among participants not receiving opioid substitution therapy who reported heroin as the main drug injected (26.9/100py, 95% CI 14.5, 50.0) and those who reported unstable housing (23.5/100py, 95% CI 7.6, 72.8), daily or more frequent injecting (22.7/100py, 95% CI 12.2, 42.2) and receptive syringe sharing (23.6/100py, 95% CI 9.8, 56.7) in the 6months prior to baseline. These data suggest that it is possible to recruit and retain at-risk PWID who adhere to study protocols and that modification of eligibility criteria may identify populations with sufficiently high HCV incidence. Results support the feasibility of large multi-centre HCV vaccine trials, including in the Australian setting.