Substance abusers account for the largest number of hepatitis C infected cases in developed countries. We describe a care model for treating current or former substance abusers with antiviral therapy for hepatitis C virus (HCV) infection. The care model involved hepatitis nurses, a psychologist, infectious disease specialist and primary care physicians. Clients met selection criteria including regular attendance at clinic appointments and social stability. Use of alcohol and illicit substances was monitored with urine toxicology screens. The association between substance use, rates of completion of therapy and rates of response were assessed using multivariable regression analyses. A total of 109 clients (75 with genotype 1/4 and 34 with genotype 2/3) received at least one injection with pegylated interferon between November 2002 and January 2006. Treatment completion rates of 61 and 74% were achieved for genotypes 1/4 and 2/3, respectively. Treatment response rates in an intention to treat analysis were 51% for genotypes 1/4 and 68% for genotypes 2/3. A positive urine toxicology screen indicating use of illicit substances 6 months prior to initiating therapy was significantly associated with lower rates of treatment completion but not lower rates of sustained virological response. A positive urine screen indicating use of alcohol prior to therapy was significantly associated with lower rates of completion and lower rates of response. Rates of completion and response are comparable to non-substance abusing populations. Antiviral therapy for HCV infection can be successful within the context of ongoing care for substance abuse for carefully selected patients.