Nine severely disabled clinically definite chronic progressive multiple sclerosis (MS) patients who had at least one determination of intra-blood-brain-barrier (BBB) IgG synthesis rate of greater than 7 mg/day (upper limit of normal = 3.3) participated in this study. Seven patients were given 1 gram of methylprednisolone sodium succinate (MP) by intravenous infusion over 30 minutes once a day for 3 days. Statistically significant (p less than .05) reduction in intra-BBB IgG synthesis (mg/day) was seen in 4/7 patients, but in only 2 were normal levels of synthesis rate (less than 3.3 mg/day) attained. Rebound of IgG synthesis to premedication rates occurred within 30 days in 2/4 patients. There was no change in intensity or pattern of cerebrospinal fluid (CSF) oligoclonal IgG bands by isoelectric focusing, immunofixation, and silver staining. A subsequent course of intrathecal methylprednisolone acetate (MPA) (80 mg twice a week for 5 weeks) was given to 5 of the 7 patients and to 2 additional patients not previously treated. In spite of signs of subarachnoid inflammation, a statistically significant depression of intra-BB synthesis, which far exceeded that from the pulse treatment occurred in all 7, including the 2 patients whose intra-BBB IgG synthesis rates were previously resistant to pulse steroid administration. Normal levels of synthesis were rapidly reached in 4/7 patients; however, an IgG synthesis rebound occurred in 3/7 patients which was just as rapid. One out of 7 patients showed a temporary reduction in the number of cathodic IgG oligoclonal bands in the CSF. Two patients required discontinuation of treatment due to aseptic meningitis in one and progressive weakness in the other. Clinically, these severely afflicted patients with fixed deficits remained unchanged with either treatment protocol. While MPA and ACTH have similar initial effect on the central nervous systems (CNS) inflammatory response in MS, the well documented risk of serious adversities with MPA prohibit its clinical use in MS in its present form.