Vitamin D has a promising role in multiple sclerosis (MS) management, and it has been found to be beneficial for patients’ mental health, which is reduced in MS patients. The aim of the present study was to conduct a systematic review of the literature to assess the influence of vitamin D supplementation on mental health in MS patients. The systematic review was registered in the PROSPERO database (CRD42020155779) and it was conducted on the basis of the PRISMA guidelines. The search procedure was conducted using PubMed and Web of Science databases and it included studies published up until September 2021. Six studies were included in the systematic review. The risk of bias was analyzed using the Newcastle–Ottawa Scale (NOS). Within the included studies, there were two studies randomized against placebo and four other prospective studies. The studies presented vitamin D interventions randomized against placebo or not randomized, while supplementation was applied for various durations—from 4 weeks to 12 months, or the studies compared patients who applied vitamin D supplementation and those who did not apply it and verified the effect of the supplementation after a number of years. The mental health outcomes that were assessed included quality of life, depression/depressive symptoms, and fatigue as an additional element. The majority of studies supported the positive influence of vitamin D on the mental health of MS patients, including the study characterized as having the highest quality (randomized against placebo with the highest NOS score). All the studies that assessed the quality of life indicated the positive influence of vitamin D while the studies that did not find a positive influence of vitamin D were conducted for depression/depressive symptoms. In spite of the fact that only a small number of studies have been conducted so far, and only two studies were randomized against a placebo, some conclusions may be formulated. The systematic review allowed us to conclude that there may be a positive effect of vitamin D supplementation in MS patients, which was stated in all of the studies analyzing quality of life, as well as in one study analyzing depressive symptoms. Considering that vitamin D deficiency is common in MS patients, and the potential positive influence of supplementation on the quality of life, supplementation should be applied at least in doses that cover the recommended intake.
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