ACTH gel and corticosteroids were given to 28 clinically definite multiple sclerosis (MS) patients to determine whether de novo central nervous system (CNS) IgG synthesis (rate and cerebrospinal fluid [CSF] IgG oligoclonal bands) could be eradicated. The most effective treatments were ACTH gel and ACTH gel followed by prednisone, all 11 patients had a significant reduction in rate (p < 0.05), which became normal in eight patients (< 3.3 mg per day). In order of effectiveness, the other drugs used were: dexamethasone or prednisone given orally, and hydrocortisone administered intrathecally. For most treatments, reduction of the rate of CNS IgG synthesis occurred within days and persisted for months after cessation of treatment. The MS CNS immune reaction was not eradicated when IgG synthesis rate became normal, because CSF IgG oligoclonal bands persisted. None of the chronic progressive, severely disabled patients demonstrated significant change in neurologic function or persistent adverse effects.