OBJECTIVE: To determine MRI predictors for cognitive outcome in patients with early relapsing-remitting multiple sclerosis (MS). METHODS: Forty-four patients recently diagnosed with clinically definite MS were followed up with clinical and cognitive evaluations at 1, 2, 5, and 7 years and underwent brain MRI including magnetization transfer (MT) imaging at baseline and 2 years. Cognitive evaluation was also performed in 56 matched healthy subjects at baseline. Cognitive testing included the Brief Repeatable Battery. Imaging parameters included lesion load, brain parenchymal fraction (BPF), ventricular fraction (VF), and mean MT ratio (MTR) of lesion and normal-appearing brain tissue (NABT) masks. RESULTS: At baseline, patients presented deficits of memory, attention, and information processing speed (IPS). Over 2 years, all magnetic resonance parameters deteriorated significantly. Over 7 years, Expanded Disability Status Scale score deteriorated significantly. Fifty percent of patients deteriorated on memory cognitive domain and 22.7%of patients on IPS domain. Seven-year change of memory scores was significantly associated with baseline diffuse brain damage (NABT MTR). IPS z score change over 7 years was correlated with baseline global atrophy (BPF), baseline diffuse brain damage, and central brain atrophy (VF) change over 2 years. CONCLUSION: The main predictors of cognitive changes over 7 years are baseline diffuse brain damage and progressive central brain atrophy over the 2 years after MS diagnosis.