Background: Oxidative stress is a driver of multiple sclerosis (MS) pathology. We evaluated the effect of coenzyme Q10 (CoQ10) on laboratory markers of oxidative stress and inflammation, and on MS clinical severity. Methods: We included 60 relapsing–remitting patients with MS treated with interferon beta1a 44μg (IFN-β1a) with CoQ10 for 3 months, and with IFN-β1a 44μg alone for 3 more months (in an open-label crossover design). At baseline and at the 3 and 6-month visits, we measured markers of scavenging activity, oxidative damage and inflammation in the peripheral blood, and collected data on disease severity. Results: After 3 months, CoQ10 supplementation was associated with improved scavenging activity (as mediated by uric acid), reduced intracellular reactive oxygen species production, reduced oxidative DNA damage, and a shift towards a more anti-inflammatory milieu in the peripheral blood [with higher interleukin (IL)-4 and IL-13, and lower eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), hepatocyte growth factor (HGF), interferon (IFN)-γ, IL-1α, IL-2R, IL-9, IL-17F, macrophage inflammatory proteins (MIP)-1α, regulated on activation-normal T cell expressed and secreted (RANTES), tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF). Also, CoQ10 supplementation was associated with lower Expanded Disability Status Scale, fatigue severity scale, Beck’s depression inventory, and the visual analogue scale for pain. Conclusions: CoQ10 supplementation improved scavenging activity, reduced oxidative damage, and induced a shift towards a more anti-inflammatory milieu, in the peripheral blood of relapsing–remitting MS patients treated with 44μg IFN-β1a 44μg. A possible clinical effect was noted but deserves to be confirmed over longer follow ups.