Depression is a suspected side effect of multiple sclerosis (MS) treatment with interferon beta-1a. However, this has not been confirmed by rigorous studies. Several psychological symptom rating scales were completed during the PRISMS clinical trial of subcutaneous interferon beta-1a (Rebif) for relapsing-remitting MS. We conducted an analysis of these data in order to determine whether symptom elevations were associated with treatment. The PRISMS clinical trial included 560 subjects from 22 centres in nine countries. There were two active treatment arms (44 mcg x 3 and 22 mcg x 3 subcutaneously three times per week) and a placebo group. Two hundred and sixty-seven of these subjects were enrolled at English speaking study centres, where psychiatric symptom ratings were obtained at baseline, 6, 12, 18 and 24 months using the Center for Epidemiological Studies Depression Rating Scale (CES-D), the General Health Questionnaire (GHQ) and the Beck Hopelessness Scale (BHS). After randomization, the groups completing these scales were similar in terms of age, gender, EDSS, duration of illness and employment status. Median CES-D scores in the high dose, low dose and placebo groups at baseline were also similar: 8.0, 7.0 and 8.0, respectively. After 6 months of treatment the median change in CES-D score was zero in all three groups. The proportion of subjects exceeding the traditional CES-D cut-point for clinically significant depression (> 15) after 6 months of treatment was strongly associated with pre-treatment depression (RR 2.9, 95% C.I.: 1.8-4.7), but not with treatment group (chi-square=1.64, d.f.=2, P=0.44). The results were comparable at 12, 18 and 24 months and when ratings from the other scales were evaluated. This analysis confirms that depression is common in persons with MS: the incidence of CES-D depression in the first 6 months of follow-up was 15.6%. However, no evidence of increased depressive symptomatology was observed in association with interferon beta-1a (Rebif).