Psychiatric disorders, especially depression, are frequent in patients with multiple sclerosis (MS). They are attributed both to the psychosocial impact of a chronic, usually progressive, disabling illness and to cerebral demyelination. Besides, drugs such as corticosteroids and possibly interferon (IFN) may also have depressogenic effects. Major depressive disorders and/or suicidal ideation are a major concern and efforts to identify and minimize these reactions are of much importance. Psychiatric side effects, particularly depression, are widely reported with IFN-α and have been suspected with IFN-β but are not yet fully established. Our review of the literature revealed that most studies discard an association between IFN-β and depression or suicide. However, few patients, especially those with a history of depression, might be at higher risk for depression when treated with IFN-β. Overall, considering the uncertainty of a link between IFN-β and depression and/or suicide, as well as the complete remission of psychiatric complications after IFN discontinuation and/or antidepressant treatment, physicians should closely monitor the psychiatric status of patients, but should not refrain from including them in IFN-β treatment programs, even when they have past or present depression.