Background: Disability accumulation in progressive multiple sclerosis (MS) results from inflammatory and neurodegenerative mechanisms. In animal models of MS, lithium acts to reduce inflammatory demyelination, and in models of neurodegenerative diseases, lithium also slows neuronal death. Prospective studies of lithium in MS patients have not been previously undertaken. Objective: To determine the tolerance and feasibility of using low-dose (150–300 mg/daily) lithium as a pharmaceutical intervention in a cohort of subjects with progressive MS, and to gauge preliminary effects of lithium on change in brain volume over time. Methods: Patients with primary or secondary progressive MS were recruited into a 2-year, single-blind crossover trial in which subjects were randomly assigned to take lithium in year 1 or 2. The primary outcomes of interest were tolerance of lithium and percentage brain volume change (PBVC) on vs. off lithium. Secondary outcomes included relapse rates, disability changes, and self-report scales assessing fatigue, mood, and quality of life (QOL). Results: Of 24 screened patients, 23 were randomized to take lithium during year 1 (n = 11) or 2 (n = 12). Two subjects discontinued the trial due to lithium side effects. Other reasons for discontinuation included personal reasons (n = 2), worsening MS (n = 1), and development of multiple myeloma (n = 1). For the 17 who completed the trial, change in PBVC on lithium (+0.107) did not significantly differ from the observation period (-0.355, p = 0.346). Disability measured by Expanded Disability Status Scale and MS Functional Composite did not differ by lithium treatment status. On patient reported measures of mental well-being, subjects reported fewer depressive symptoms on the Beck Depression Inventory (12.3 vs. 15.8, p = 0.016) and more favorably on the mental domains of the MSQOL inventory (56.7 vs. 52.4, p = 0.028). Conclusions: Low-dose lithium is well tolerated in persons with MS. Taking lithium did not result in differences in PBVC, relapses, or disability, but conclusions were limited by study design and sample size. Despite concern for lithium-associated neurological side effects, subjects taking lithium did not report worsened fatigue or physical well-being. On measures of mood and mental health QOL, subjects scored more favorably while taking lithium. Clinicaltrials.gov identifier: NCT01259388.