Objective To compare clinical responses to once-weekly intramuscular interferon-β-1 a [IFNβ-1 a, Avonex^®, Biogen] in multiple sclerosis (MS) patients with baseline Expanded Disability Status Scale (EDSS) ≤ 3.5 or > 3.5. Methods Patients with relapsing-remitting MS (RRMS), 124 with baseline EDSS ≥ 3.5 and 64 RRMS patients with EDSS > 3.5, were consecutively recruited to receive IFNβ-1 a 30 μg as a once weekly injection for 18 months. The primary endpoint of the study was the number of patients in each group with sustained worsening in disability, defined as 1-point deterioration in EDSS that persisted for at least 6 months during the 18 month follow-up period. Subordinate endpoints included relapse rates and the number of treatment dropouts. Results Among patients with baseline EDSS ≤ 3.5, 16.9 % experienced a deterioration in EDSS of at least 1 point ; 22.5 % experienced a deterioration of at least 0.5 %. Corresponding rates in patients with baseline EDSS > 3.5 were 23.4 % and 29 % respectively (no significant differences between patients stratified according to baseline EDSS status). The proportion of patients discontinuing therapy was significantly higher in patients with baseline EDSS > 3.5 than in those with baseline EDSS ≤ 3.5 (16/64 versus 12/124 ; p = 0.005). At the conclusion of follow-up, IFNβ-1 a therapy was associated with a 31.7 % reduction in relapse rate in patients with baseline EDSS ≤ 3.5 and a 37 % reduction in those with baseline EDSS > 3.5 (difference not significant). Conclusions During 18 months of treatment and follow-up, no difference was observed in clinical responses to IFNβ-1 a between RRMS patients with mild and moderate disability but discontinuation of therapy was more frequent in the more disabled group.