The objectives were twofold: a) to explore a possible association between major depression and treatment with interferon beta-1b in patients with multiple sclerosis; and b) to investigate whether putative antecedent risk factors such as a previous psychiatric history and a family history of affective illness influence the prevalence of major depression post-treatment with interferon beta-1b. Forty-two patients with relapsing-remitting MS underwent neurological examination and were interviewed with the Structured Clinical Interview for Axis 1 DSM-IV Disorders prior to starting interferon beta-1b and thereafter at 3, 6 and 12 months. Ethical considerations dictated that patients diagnosed with major depression received anti-depressant medication. At index assessment, 21.4 % of the sample were diagnosed with a major depression, the figures falling to 17.5 %, 11.4 % and 6.3 % at 3, 6 and 12 months respectively. The majority of subjects with a major depression had a history of psychiatric illness prior to treatment with interferon beta-1b. A family history of affective disorder was not associated with a significantly increased rate of major depression either before or after treatment with interferon beta-1b. While the study's methodology did not address causality, the data demonstrate that major depression post-treatment with interferon beta-1b is linked to a history of psychiatric illness prior to starting treatment. The threefold decline in prevalence rates for major depression over the course of a year demonstrates a good response to anti-depressant medication and possible beneficial effects of interferon beta-1b on mood.