Proposed beta-interferon (IFNbeta) treatment failure criteria for patients with relapsing-remitting multiple sclerosis (RRMS) have not been validated in clinical practice. This study aimed to establish (a) whether IFNbeta attenuated accumulation of fixed disability in comparison to a cohort of matched historical control subjects from the Sylvia Lawry centre for MS research, and (b) whether relapse-based treatment failure criteria or clinical and demographic variables had predictive value for the accumulation of fixed disability. Of the 175 IFNbeta-treated RRMS patients, 60 (34%) developed accumulation of fixed disability over a median of five years follow-up, which was significantly less than the rate of accumulation of fixed disability in the control group (P<0.0001). Any relapse in the treatment period predicted accumulation of fixed disability with a sensitivity of 80% and specificity of 43%; patients totally relapse free were less likely to develop accumulation of fixed disability (P <0.002). Multivariate analysis confirmed that a greater risk of accumulation of fixed disability was conferred by a higher Expanded Disability Status Scale (EDSS) score starting IFNbeta (P=0.02), and by failure of IFNbeta to completely suppress relapses (P=0.004). In conclusion, IFNbeta therapy reduced the accumulation of fixed disability in a cohort of RRMS patients, followed for a median of five years. Higher baseline EDSS and failure of complete relapse suppression were associated with a significantly greater likelihood of accumulation of fixed disability.