Hepatitis C viral infection is a global health problem that affects approximately 4 million people in the United States. Combination treatment with pegylated interferon (IFN)-alpha plus ribavirin has been shown to be most effective in treating patients with chronic hepatitis C (CHC). Despite its efficacy, one of the most common side effects of this regimen is depression. Whereas IFN-alpha has been found to induce depression in chronic myelogenous leukemia, melanoma, and renal cell carcinoma, CHC patients may be especially prone to develop IFN-induced depression. This review includes a summary of differences between IFN-alpha and IFN-beta and addresses whether pegylation of IFN (versus nonpegylated IFN) gives rise to a treatment with reduced potential to induce depressive symptoms. Consideration is also given to evidence showing that treatment with ribavirin may contribute to IFN-induced depression. Thyroid disorders and anemia (as well as other medical conditions) have also been associated with IFN exposure and may account for some incidences of depression in CHC patients. Evidence is reviewed indicating that prior psychiatric and mood disorders (especially previous episodes of major depressive disorder), just prior to IFN treatment, contribute to the propensity to develop depression during treatment. In addition, a brief description is provided of potential biological mechanisms of IFN-induced depression (ie, monoamines, hypothalamic-pituitary-adrenocortical [HPA] axis, proinflammatory cytokines, peptidases, intercellular adhesion molecule-1, and nitric oxide). Finally, a discussion is provided on the use of antidepressants as a preventative versus restorative treatment, including a commentary on risks of using antidepressants in this patient population.