Functional imaging studies have demonstrated a relationship between fatigue and altered cerebral activation patterns in multiple sclerosis patients, but no relationship between fatigue and brain atrophy has been demonstrated. We hypothesized that the subjective complaint of fatigue would predict the severity of destructive brain pathology. We assessed the relationship between fatigue and brain atrophy longitudinally in a cohort of 134 patients previously enrolled in a 2-year clinical trial of interferon beta-1a and re-evaluated 8 years after randomization into the trial. Brain atrophy was measured using the brain parenchymal fraction (BPF), and disability was measured using the Multiple Sclerosis Functional Composite at baseline, year 2 and year 8. Fatigue was measured using the Sickness Impact Profile's Sleep and Rest Scale (SIPSR) at baseline, year 2 and year 8. Linear regression analyses were used to assess the relationship between changes in fatigue and atrophy progression. Worsening fatigue on the SIPSR during the initial 2 years was significantly associated with progressive brain atrophy over the subsequent 6 years. The relationships between fatigue and brain atrophy were independent of changes in disability, mood, or other MRI characteristics. This suggests that the subjective complaint of fatigue is linked to destructive pathologic processes in RRMS patients.