MBP8298 is a synthetic peptide with a sequence corresponding to amino acid residues 82–98 of human myelin basic protein (DENPVVHFFKNIVTPRT). It represents the immunodominant target for both B cells and T cells in multiple sclerosis (MS) patients with HLA haplotype DR2. Its administration in accordance with the principle of high dose tolerance results in long‐term suppression of anti‐myelin basic protein (MBP) autoantibody levels in the cerebrospinal fluid (CSF) of a large fraction of progressive MS patients. MBP8298 was evaluated in a 24‐month placebo‐controlled double‐blinded Phase II clinical trial in 32 patients with progressive MS. The objective was to assess the clinical efficacy of 500 mg of MBP8298 administered intravenously every 6 months, as measured by changes in Expanded Disability Status Scale (EDSS) scores. Contingency analysis for all patients at 24 months showed no significant difference between MBP8298 and placebo‐treatments (n = 32, P = 0.29). Contingency analysis in an HLA Class II defined subgroup showed a statistically significant benefit of MBP8298 treatment compared with placebo in patients with HLA haplotypes DR2 and/or DR4 (n = 20, P = 0.01). Long‐term follow‐up treatment and assessment of patients in this responder group showed a median time to progression of 78 months for MBP8298 treated patients compared with 18 months for placebo‐treatment (Kaplan–Meier analysis, P = 0.004; relative rate of progression = 0.23). Anti‐MBP autoantibody levels in the CSF of most MBP8298 treated patients were suppressed, but antibody suppression was not predictive of clinical benefit. Anti‐MBP autoantibodies that reappeared in the CSF of one patient at 36 months, whilst under treatment with MBP8298, were not reactive with the MBP8298 peptide in vitro. The identification of a responder subgroup (62.5% of the patients in this study) enables a more efficient design of a large confirmatory clinical trial of MBP8298. The probability that patients with other less common HLA‐DR haplotypes will respond to this treatment should not be ignored.