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The Major Depression Inventory (MDI) was used to estimate the value of routine medical interviews in diagnosing major depression among patients receiving peginterferon alfa‐2a and ribavirin therapy for chronic hepatitis C virus (HCV) infection (n = 325). According to criteria from the MDI and Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV), 19 patients (6%) had major depression at baseline. An additional 114 (37%) developed depression while on HCV combination therapy, with baseline MDI score and female sex independently predicting the emergence of major depression during treatment in a multivariate analysis. Only 36 (32%) of the 114 patients developing major depression according to MDI/DSM‐IV criteria were correctly diagnosed during routine medical interviews. The emergence of major depression frequently led to premature discontinuation of peginterferon/ribavirin therapy, and an …