BACKGROUND: Brain atrophy in multiple sclerosis (MS) patients is present since the very early stages of the disease and it has been related to long-term disability. OBJECTIVE: To estimate brain volume (BV) at 15 years after a clinically isolated syndrome (CIS) and to evaluate its relationship with disease outcomes. METHODS: From a prospective cohort including patients presenting with a CIS, 54 patients with a brain magnetic resonance imaging (MRI) performed 15 years after CIS were included. Brain parenchymal fraction (BPF), grey matter fraction (GMF) and white matter fraction (WMF) at 15-year follow-up were obtained. Regression analyses were conducted to predict BV loss and reaching an Expanded Disability Status Scale (EDSS) of 3.0 in that 15-year period. RESULTS: In multivariable analyses, lower values of BPF and WMF were significantly associated with being male, presenting 3–4 Barkhof criteria at baseline, presenting a second relapse, and with a decision to start treatment. In the multivariable logistic regression analysis, only lower GMF was associated with a greater risk of reaching EDSS 3.0 (odds ratio (OR) = 0.24, p = 0.028). CONCLUSION: Lower BPF and WMF 15 years after CIS are associated with previous markers of inflammatory disease. Lower GMF 15 years after a CIS is associated with an increased risk of reaching an EDSS of 3.0
