BACKGROUND: Magnetization transfer imaging has the potential to provide a surrogate marker for progression in primary progressive multiple sclerosis (PPMS). OBJECTIVES: To investigate whether brain magnetization transfer imaging, T2 lesion load, and atrophy changes over 3 years reflect concurrent clinical changes, and which baseline imaging measure best predicts progression over 3 years in early PPMS. DESIGN: Prospective study. SETTING: National Hospital for Neurology and Neurosurgery and the Institute of Neurology, London, England. PATIENTS: Forty-seven patients with PPMS (of whom 43 completed the study) and 18 control subjects. INTERVENTIONS: Brain magnetization transfer imaging (including T2-weighted images) and volume sequences every 6 months for 3 years. MAIN OUTCOME MEASURES: Changes in Expanded Disability Status Scale (EDSS) score and associations with rate of change in imaging variables. RESULTS: More rapid decline in gray matter mean and peak location magnetization transfer ratio and T2 lesion load increase were associated with greater rates of progression on the EDSS. Baseline gray matter peak height magnetization transfer ratio best predicted progression over 3 years. CONCLUSION: Gray matter magnetization transfer ratio meets many of the criteria for a surrogate marker of progression in early PPMS.