Objective Treating acute hepatitis C (HCV) in injection drug users (IDUs) is complicated by a high prevalence of psychiatric comorbidities that may lead to increased risk for depressive complications of interferon treatment. Effective screening strategies are needed to help non-psychiatric clinicians identify depressive disorders. Methods Thirty IDUs with acute HCV completed the Beck Depression Inventory (BDI), underwent a psychiatric examination, and were randomized to 24 weeks of pegylated interferon treatment (IFA) or observation (OBS). Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the BDI for diagnosing depression (with a cutoff >10) were calculated. The psychiatrist's diagnosis was used as the gold standard. Depression severity was assessed over time with the BDI. Results Forty-seven percent of individuals met criteria for a depressive disorder. Sensitivity (91%) and NPV (92%) were high for the BDI; specificity (58%) and PPV (56%) were low. BDI worsened in 2 patients completing the study (one IFA, one OBS); two IFA patients were discontinued for possible depression-related complications. At baseline, subject-rated fatigue was associated with alanine aminotransferase level. Conclusion The BDI is an adequate tool for ruling out depressive disorders in active IDUs with acute HCV, but specificity is low. Psychiatric consultation is recommended for all active IDUs being considered for acute HCV treatment.