Objective: To determine 30-year brain atrophy rates following clinically isolated syndromes and the relationship of atrophy in the first 5 years and clinical outcomes 25 years later. Methods: A cohort of 132 people who presented with a clinically isolated syndrome suggestive of multiple sclerosis (MS) were recruited between 1984-1987. Clinical and MRI data were collected prospectively over 30 years. Widths of the third ventricle and the medulla oblongata were used as linear atrophy measures. Results: At 30 years, 27 participants remained classified as having had a clinically isolated syndrome, 34 converted to relapsing remitting MS, 26 to secondary progressive MS and 16 had died due to MS. The mean age at baseline was 31.7 years (SD 7.5) and the mean disease duration was 30.8 years (SD 0.9). Change in medullary and third ventricular width within the first 5 years, allowing for white matter lesion accrual and Expanded Disability Status Scale increases over the same period, predicted clinical outcome measures at 30 years. 1 mm of medullary atrophy within the first 5 years increased the risk for secondary progressive MS or MS related death by 30 years by 583% (OR 5.83, 95% CI 1.74 to 19.61, p<0.005), using logistic regression. Conclusions: Our findings show that brain regional atrophy within 5 years of a clinically isolated syndrome predicts progressive MS or a related death, and disability 25 years later.