We studied 60 patients receiving a 1-year course of interferon (IFN)-alpha therapy for chronic viral hepatitis. Patients underwent psychiatric assessment before starting the IFN-alpha therapy, and monthly throughout the therapy, using the Structured Clinical Interview for the DSM-III-R, the 17-item Hamilton Depression Rating Scale, the Beck Depression Inventory and the Spielberg State and Trait Anxiety Inventory. Five patients had a baseline diagnosis of major depression and 18 (30%) developed an IFN-alpha-induced psychiatric adverse effect; 12 of these 23 patients received psychopharmacological treatment (patients and clinicians jointly decided the need for treatment). Two of the five patients with baseline depression started an antidepressant treatment (paroxetine) together with the IFN-alpha and successfully completed the IFN-alpha therapy. Ten patients received treatment for the IFN-alpha-induced psychiatric adverse effects (depression in five patients, anxiety in two patients, severe irritability in two patients and insomnia in one patient). Depression was treated with paroxetine, amisulpride or levosulpiride; anxiety and insomnia were treated with benzodiazepines; and irritability was treated with thioridazine. Individual response to medications was measured with the Clinical Global Impression scale. Of the patients with IFN-alpha-induced depression, two received paroxetine (one showed a good response), two received amisulpride (one showed a good response) and one did not respond to levosulpiride but responded to paroxetine. The patients experiencing anxiety or insomnia responded well to benzodiazepines. One patient showed a good response, and one a poor response, to thioridazine for irritability. Only one patient interrupted the therapy because of psychiatric adverse effects. Overall, the 12 patients that received psychopharmacological treatment developed less severe psychopathological symptoms during the IFN-alpha therapy compared to the 11 patients who had untreated baseline depression or untreated IFN-alpha-induced psychiatric adverse effects. Thus, psychopharmacological management can successfully treat psychiatric symptoms in patients who are receiving IFN-alpha.