The immunological effects of high-dose methylprednisolone in attacks of multiple sclerosis and acute optic neuritis have only been examined in a few randomized, controlled trials. We studied immunological changes in 50 patients with optic neuritis or multiple sclerosis who underwent lumbar puncture before and 1 week after completing a 15-day course of oral high-dose methylprednisolone treatment. Treatment resulted in a decrease in the concentration of myelin basic protein, a decrease in the serum concentration of immunoglobulin G (IgG) and intrathecal IgG synthesis, an increase in the cerebrospinal fluid concentration of transforming growth factor-beta1, and changes in the expression of CD25, CD26, and human leukocyte antigen-DR (HLA-DR) on CD4 T-cells. No effect was seen on the cerebrospinal fluid leucocyte count or the cerebrospinal fluid activity of matrix metalloproteinase-9 (MMP-9). The lack of a persistent effect on cerebrospinal fluid leucocyte recruitment and MMP-9 activity, despite changes in IgG synthesis, T-cell activation, and cytokine production, suggests that modulation of the function of inflammatory cells may contribute to the clinical efficacy of oral high-dose methylprednisolone treatment in optic neuritis and multiple sclerosis.