Despite current injecting drug users (IDUs) being the major risk group for new hepatitis C virus (HCV) infections in most countries, they constitute a small minority of study populations in almost all studies of acute HCV infection treatment. The Australian Trial in Acute Hepatitis C (ATAHC) is examining natural history and treatment efficacy among predominantly IDU-acquired acute HCV. Recruitment is through an Australian network of primary and tertiary care sites. Eligible participants are offered treatment with pegylated-interferon alpha-2a (PEG-IFN) for 24 weeks, with both treated and untreated participants followed for up to three years. Quantitative and qualitative data on injecting behaviour is collected on study participants. Participants are regularly reviewed by a multidisciplinary team that includes the treating clinician, HCV clinic nurse, outreach worker and when necessary are referred to a drug and alcohol worker, social worker, psychiatrist or other appropriate services. A contact log records all interactions between participants and the study team. In September 2006, 121 subjects had been screened, 107 were enrolled and 75 had chosen to commence a 24-week course of PEG-IFN (HIV/HCV coinfected participants are treated with PEG-IFN/ribavirin combination therapy). Eighty per cent of ATAHC participants reported IDU within the previous six months. Recruitment is planned to continue through mid-2007. Through a series of case reports, this paper describes factors that are potential barriers to recruitment, follow-up, and treatment of IDUs in the context of acute HCV infection. PEG-IFN adherence and toxicity, current substance use or mental health issues are not presenting as the only barriers to HCV treatment. Financial and transport difficulties, isolation and social support, and legal issues have been prominent and had the potential to impact on clinic attendance and treatment success. Our work suggests that by using a multidisciplinary approach, potential barriers to recruitment and follow-up of current IDUs to HCV treatment can be effectively addressed, and this highly marginalised population can be successfully engaged and treated.