Background There is insufficient knowledge about how aerobic exercise impacts the disease process of multiple sclerosis, which is characterized by accumulation of white matter lesions and accelerated brain atrophy. Objective To examine the effect of aerobic exercise on neuroinflammation and neurodegeneration by magnetic resonance imaging and clinical measures of disease activity and progression in persons with multiple sclerosis. Patients and methods An exploratory 12-week randomized control trial including an intervention group ( n = 14, 12 weeks of aerobic exercise twice weekly) and a control group ( n = 14, continuation of usual lifestyle). Primary outcomes were magnetic resonance imaging measures (lesion load, brain structure volume change), while secondary outcomes included disability measures, blood cytokine levels, cognitive tests and patient-reported outcomes. Results The effects of aerobic exercise on whole brain and grey matter atrophy were minor. Surprisingly, the observed effect on volume (atrophy) in selected brain substructures was heterogeneous. Putaminal and posterior cingulate volumes decreased, parahippocampal gyrus volume increased, thalamus and amygdala volume remained the same, and active lesion load and count decreased. However, apart from weak improvements in walking speed and brain-derived neurotrophic factor levels, there was no effect of aerobic exercise on other clinical, cognitive or patient-reported outcomes. Conclusion These results suggest that aerobic exercise in persons with multiple sclerosis has a positive effect on the volume of some of the substructures of the brain, possibly indicating a slowing of the neurodegenerative process in these regions, but a negative impact on the volume of some other substructures, with unclear implications. Further research is needed to determine whether the slight decrease in active lesion volume and count implies an anti- inflammatory effect of aerobic exercise, and the exact significance of the heterogeneous results of volumetric assessments. LAY ABSTRACT The aim of this study was to evaluate the effects of aerobic exercise (physical exercise in the form of aerobics) on people with multiple sclerosis who were being treated with fingolimod. Two groups of patients with multiple sclerosis were studied: an intervention group ( n = 14) who undertook 12 weeks of exercise training, and a control group ( n = 14) who continued with their usual lifestyle. Magnetic resonance imaging, bloodwork analysis and some other clinical assessments were performed before and after the 12-week period, and the patients completed several questionnaires about their wellbeing and accompanying symptoms of multiple sclerosis. The results suggest that aerobic exercise (combined with appropriate phar...