A randomized placebo-controlled trial of interferon-beta1b was performed on 718 patients with secondary progressive multiple sclerosis with follow-up of up to 3 years. In addition to clinical variables, serial magnetic resonance imaging (MRI) studies were performed to determine the effect of treatment on the pathological evolution of the disease. All patients eligible for MRI had annual proton density/T2-weighted brain scans from which total lesion volume was measured and the number of new and enlarging lesions noted. A subgroup of 125 patients also underwent monthly gadolinium-enhanced and proton density/T2-weighted brain MRI from months 0 to 6 and 18 to 24 to determine the effect of treatment on the frequency of new lesion activity, defined as new enhancing lesions and new/enlarging T2 lesions not enhancing with gadolinium. The difference in total lesion volume between treatment groups was highly significant. In the placebo group, there was an increase of 15% from baseline to last scan, whereas in the interferon-beta1b group, a reduction of 2% was seen. Within the placebo group, there was a significant year-on-year increase in total lesion volume, with a mean increase of 16% at year 3 compared with baseline. In the treated group, there was a significant reduction at year 1 (4%) and year 2 (5%) compared with baseline; the 2% decrease at year 3 was not significant. The number of new or enlarging proton density/T2 lesions was also significantly reduced by treatment. In the frequent MRI subgroup, treatment was associated with a significant 65% reduction in new lesion activity between months 1 and 6, and 78% reduction from months 19 to 24. Interferon-beta1b has a substantial and sustained effect on reducing the accumulation of new inflammatory disease foci in secondary progressive MS. This therapeutic mechanism may contribute to the positive clinical benefits of treatment on the progression of sustained neurological disability and relapse activity that were also identified in this trial.