Objectives: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and magnetic resonance imaging results between trial arms and to investigate correlations between in-trial changes in Multiple Sclerosis Functional Composite (MSFC) score and magnetic resonance imaging variables and Expanded Disability Status Scale (EDSS) score evolution. Design: Five-year clinical trial follow-up. Setting: Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Autonomous University of Barcelona, Spain. Patients: Seventy-three patients received interferon beta-1b or placebo during the trial. Main Outcome Measures: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 patients, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 patients, respectively. Results: After 5 years without treatment,the interferon beta- 1bgrouphadbetter 9-Hole Peg Test (P=.02)andWordList Generation Test (P≲λτ∀.001) scores, and their magnetization transfer ratio measures in the normal-appearing white matter were significantly higher (P=.02,P=.009,andP=.03 for the mean, peak location, and peak height magnetic transfer ratios, respectively).Duringthe entirestudyperiod(from trial baseline to assessment at 5 years without treatment), the placebogroupshoweda greater decrease in brain parenchymal fraction (P=.004). The in-trial increase of lesions correlated with the worsening of the EDS Sscore during the 5-year period without treatment (P=.004). Conclusions: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis. ©2011 American Medical Association. All rights reserved.