The brain ventricles are part of the fluid compartments bridging the CNS with the periphery. Using MRI, we previously observed a pronounced increase in ventricle volume (VV) in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here, we examined VV changes in EAE and MS patients in longitudinal studies with frequent serial MRI scans. EAE mice underwent serial MRI for up to 2 months, with gadolinium contrast as a proxy of inflammation, confirmed by histopathology. We performed a time-series analysis of clinical and MRI data from a prior clinical trial in which RRMS patients underwent monthly MRI scans over 1 year. VV increased dramatically during preonset EAE, resolving upon clinical remission. VV changes coincided with blood-brain barrier disruption and inflammation. VV was normal at the termination of the experiment, when mice were still symptomatic. The majority of relapsing-remitting MS (RRMS) patients showed dynamic VV fluctuations. Patients with contracting VV had lower disease severity and a shorter duration. These changes demonstrate that VV does not necessarily expand irreversibly in MS but, over short time scales, can expand and contract. Frequent monitoring of VV in patients will be essential to disentangle the disease-related processes driving short-term VV oscillations from persistent expansion resulting from atrophy.