A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 × l06 IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.