60-90% of patients with intravenous drug abuse are chronically infected with the hepatitis C virus (HCV). Antiviral treatment with pegylated interferon-alfa (IFN-α) plus ribavirin is often complicated by psychiatric adverse events, significantly affecting patients adherence. Depression, anxiety, fatigue and irritability as typical IFN-α associated side effects occur in 30-80% during antiviral treatment of hepatitis C. Patients with drug addiction were shown to have an increased risk to discontinue HCV-treatment early in the first three treatment months, where most neuropsychiatric side effects appear. Especially vegetative side effects in the first few weeks (“flu-like syndrome”) can be misunderstood as withdrawal symptoms, followed by a relapse in drug or alcohol abuse. As a consequence methadone substitution treatment was found to be the best therapeutic setting. In addition side effect management should be intensified during first three months of HCV-treatment. Most data for the management of specific IFN-α associated side effects are available for depressive syndromes. Antidepressants (especially serotonin-reuptake-inhibitors) such as citalopram were shown to significantly reduce IFN-α associated depressive symptoms. A pre-emptive treatment with antidepressants should be considered at least for patients with additional psychiatric risk factors before interferon-based therapy is started. Because data from prospective controlled trials are lacking, management of other side effects such as sleep disturbances, irritability, psychotic syndromes, mania, suicidal thoughts and delirious syndromes should follow general psychiatric treatment recommendations. Overall, the psychiatric adverse event profile of interferon-based therapy for HCV-infected patients with drug addiction is considerable and requires active management and knowledge about psychiatric medical therapy.