We assessed neuropsychological function longitudinally in 30 MS patients who participated in the pivotal trial of interferon beta-1b (IFN-beta-1b). Nine patients received high-dose IFN-beta-1b (8.0 million units), eight low-dose IFN-beta-1b (1.6 MIU), and 13 placebo. There was significant improvement in Wechsler Memory Scale Visual Reproduction-Delayed Recall scores between years 2 and 4 of the trial in MS subjects receiving high-dose IFN-beta-1b. Motoric performance, MRI lesion area, and depression rating scores did not correlate with this finding. Comparison of MRI at baseline and at years 2 and 4 revealed significant changes over time for the total cohort (p < 0.02). Mean lesion area in the high-dose group did not change over time, whereas the low-dose and placebo groups had increases in total lesion area of 28 and 36%, respectively, at year 4. Expanded disability status scale scores did not change significantly between years 2 and 4 of the trial, nor did they correlate with MRI lesion area at any assessment point. We conclude that high-dose IFN-beta-1b improves delayed visual reproduction test performance in MS patients, a finding unlikely to be explained by practice effects or brain lesion area.