Fatigue is a highly prevalent and disabling symptom in MS that has no current FDA approved therapy. Stimulants such as amantadine, methylphenidate and modafinil are commonly used “off-label” to treat fatigue in people with MS (PwMS), but their use is limited by side effects and limited efficacy. Similar to the 70-90% of the non-Veteran PwMS who are impacted by fatigue adversely, Veterans with MS (VwMS) are affected too. Despite the wide spread use of MS disease modifying therapies, fatigue remains a significant cause of disability, non-employability and poor quality of life in both VwMS and PwMS. There is therefore an urgent need to develop novel ways to impact fatigue in MS. While the origins of MS related fatigue is likely complex and multifactorial, we believe that mitochondria dysfunction and resultant neuronal energy depletion may be an important contributor to fatigue in MS. A recent study evaluated the efficacy of the mitochondrial cofactor and antioxidant supplement, coenzyme Q10 (CoQ10, also known as ubiquinol/ubiquinone), for fatigue and mood improvement in MS. This study showed significant albeit modest improvement in fatigue and mood in CoQ10 treated subjects as compared to placebo. Oral Mitoquinone (MitoQ) is a more mitochondrial-specific form of coenzyme CoQ10 in which CoQ10 has a covalently linked sidechain that imparts a stronger affinity for the mitochondria. The objective of this clinical trial is to evaluate the potential beneficial effects of MitoQ on MS fatigue. This research purposes to develop novel ways to impact fatigue in MS and ultimately to determine whether treatment targeting mitochondrial function have a potential to alter the symptoms or course of MS. The central hypothesis is that MitoQ with its mitochondrial affinity will improve MS related fatigue as well as cognition, quality of life and mood by improving mitochondrial function and resultant neuronal energy depletion in neurons. We propose the following aims: Specific Aim 1: Determine whether VwMS who receive oral MitoQ in comparison to those who receive placebo have less fatigue after a 12-week treatment period as measured by MFIS Score. Specific Aim 2: Determine whether VwMS who receive oral MitoQ in comparison to those who receive placebo have improved cognitive function, quality of life and depression using Symbol Digit Modality Test (SDMT), MS Impact Scale -29 (MSIS-29) and the Beck Depression Inventory–Fast Screen scores respectively. Specific Aim 3: Determine the safety and tolerability of MitoQ in VwMS using side effects and blood tests. Specific Aim 4: Determine whether plasma MitoQ levels in VwMS treated with MitoQ correlate with clinical outcomes of fatigue, cognitive function, quality of life and depression and with blood based inflammatory immune and oxidative stress biomarkers. Research Design: We propose to conduct a double-blind, placebo-controlled, pilot trial to compare the administration of a 20 and 40 mg once a day dose of MitoQ to a placebo...