Background: Clinical disability is among the risk factors of a more severe coronavirus disease of 2019 (COVID-19) course in patients with multiple sclerosis (PwMS), but might provide an insensitive reflection of actual tissue pathology. Brain volume loss has emerged as a magnetic resonance imaging (MRI) proxy of neurodegeneration in PwMS. Our main objective was to investigate whether brain volume predicts COVID-19 severity in PwMS. Methods: Clinical data of PwMS followed at the Belgian National Multiple Sclerosis (MS) Center in Melsbroek are collected in a local database in case of COVID-19 diagnosis. One hundred ninety-eight unique PwMS with a suitable 3D brain MRI available, conducted maximally 24 months before their COVID-19 infection, were included. Results: An unfavorable outcome due to COVID-19 was noted in fourteen PwMS (hospitalization: 7.1 \%, death: 0.5 \%). Neither global nor regional normalized brain volumes predicted COVID-19 severity. Similar results were obtained in patients fulfilling the criteria for benign MS. Being unprotected by vaccination was the only variable significantly associated with a poor COVID-19 outcome (OR 3.7; CI 1.2–10.2). We observed a significant worsening of Symbol Digit Modality Test performance in PwMS with the lowest (Q4) whole brain volume, as compared to those with the highest (Q1) (2.2 ± 8.5 versus −1.2 ± 9.1; P = 0.037). Conclusion: Brain volume does not predict COVID-19 outcome in PwMS, including those with benign MS. Unvaccinated individuals remain susceptible to developing a more severe infection. PwMS with the most profound pre-existing brain atrophy may be at risk for cognitive deterioration after COVID-19.