The prevalence of depression is high among injection drug users (IDUs) and among those infected with the hepatitis C virus (HCV). Moreover, one of the drugs used in the standard treatment for HCV infection (interferon) has been known to exacerbate underlying psychiatric disorders such as depression and has been associated with the development of major depressive disorder among HCV-infected patients. For these reasons, the most recent National Institutes of Health consensus statement on the management of HCV infection recommends the identification and treatment of depression prior to the start of HCV treatment. This study aimed to examine the extent of current moderate/severe depressive symptoms in a cohort of HCV-infected IDUs as measured by two screening tools, the Center for Epidemiologic Studies Depression Scale (CES-D) and the Beck Depression Inventory (BDI). Subjects were participants in a multisite behavioral intervention trial among HCV-seropositive, human immunodeficiency virus-negative IDUs aged 18-35 years; the trial was designed to prevent secondary transmission of HCV and to enhance uptake of HCV treatment. Baseline data on demographics, risk behaviors, depression, alcohol use, and health care utilization were measured via audio computer-assisted self-interview. A factor analysis was conducted on each scale to examine the clustering of items used in each to measure depressive symptoms. Baseline depressive symptoms, as measured via the CES-D and the BDI, were also compared using Pearson's correlation coefficient. Of 193 HCV-infected individuals enrolled to date, 75.6% were male, and 65.3% were white. Median age was 25.8 years. Factor analyses revealed that these scales measured depression differently; a distinct somatic component was present in the BDI, but not the CES-D. Using cutoff scores of 23 for the CES-D and 19 for the BDI, 44.0% and 41.5% of the participants were identified as having moderate/severe depressive symptoms, respectively. Over half (56.0%) were identified as having depressive symptoms by either scale. However, there was only moderate agreement between the two scales (kappa=0.46). Depressive symptoms were highly prevalent in this cohort of HCV-infected IDUs. Results indicated that both scales should be used in tandem to have the most sensitive detection of depressive symptoms, thereby maximizing the potential for HCV treatment success.