Approximately 85% of multiple sclerosis (MS) cases begin as clinically isolated syndromes (CIS). Results from the Controlled High-Risk Subjects Avonex((R)) Multiple Sclerosis Prevention Study (CHAMPS) demonstrated that, in patients with CIS, treatment with intramuscular (IM) interferon beta-1a (IFNbeta-1a) 30 mug once weekly delayed conversion to clinically definite MS (CDMS) in the total population and in subgroups based on presenting syndromes and baseline magnetic resonance imaging (MRI) characteristics. Changes to clinical and MRI risk classification of presenting symptoms in recent studies prompted reanalysis of CHAMPS data. Presenting syndromes were assessed using a derived algorithm that stratifies patients into mono- or multifocal categories based on functional system scores. The ability of IM IFNbeta-1a to delay progression to CDMS in subgroups based on clinical presentation and MRI characteristics was assessed. Reanalysis of CHAMPS patients showed that 30% could be classified by clinical criteria as having multifocal disease at baseline. IM IFNbeta-1a initiated at a first demyelinating attack delayed CDMS in monofocal patients (P = 0.0013), patients with or without gadolinium-enhancing lesions (P = 0.0007, P = 0.0405) and patients with at least nine T2 lesions at baseline (P = 0.0044). These data confirm that IM IFNbeta-1a delays conversion to CDMS in patients with CIS.