Objective: To investigate if high-dose intravenous interferon-beta (IFNb) in high-titer neutralizing antibody-(NAb)-positive multiple sclerosis (MS) patients reduces NAb titers to less than 100 neutralizing units (NU) - presumably by induction of immune tolerance (IT) - and restores IFNb bioavailability measured by myxovirus protein A (MxA) concentrations. Background IFNb is associated with the generation of NAbs affecting treatment efficacy. Successful IT induction has been shown for hemophilia patients with NAbs against recombinant factor-VIII by high-dose intravenous administration of factor-VIII. Design/Methods: 9 MS patients, with a NAb titer of >=500 NU, received 48 MIU IFNb-1b intravenously once weekly over 3 months. Blood samples were collected at screening, monthly before and 4 hours after infusions, and at follow-up after 6 months for NAb and MxA measurement. Disease activity was monitored by brain MRI and EDSS assessments. Results: Median NAb titer at baseline was 1429 NU. Titers determined before each infusion did not change over the treatment period. There was a significant decrease of titers four hours after each infusion. NAb titers at follow-up did not significantly differ compared to titers at screening. Comparing NAb titers after 3 months to baseline, 4 patients showed increased titers by 654 NU and 5 decreased titers by 235 NU indicating a possible responder group. MxA levels were significantly elevated after all IFNb infusions reaching a median value of 206. MRI data are currently being analyzed. Conclusions: Weekly intravenous IFNb induced short-term bioactivity in patients with high NAb titers but failed to induce long-term reversion of NAb although in some patients a trend towards reversion was observed. Supported by: Bayer Schering Pharma. Disclosure: Dr. Hegen has received personal compensation for activities with Bayer PHarmaceuticals Corporation, Schering-Plough Corporation, Biogen Idec, Merck Serono as speaker. Dr. Guger has nothing to disclose. Dr. Harrer has nothing to disclose. Dr. Hoelzl has nothing to disclose. Dr. Kraus has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck-Serono, Novartis, Genzyme Corporation as a consultant. Dr. Kraus has received research support from Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck Serono, Novartis, Genzyme Corporation. Dr. Skrobal has nothing to disclose. Dr. Schautzer has nothing to disclose. Dr. Schmidegg has nothing to disclose. Dr. Deisenhammer has received personal compensation for activities with Biogen Idec, Merck Serono, Bayer and Sanofi. Dr. Deisenhammer has received research support from Bayer HealthCare.