Multiple sclerosis (MS) is a chronic central nervous system disease that is associated with progressive loss of myelin and subsequent axonal degeneration. Cholesterol is an essential component of mammalian cellular and myelin membranes. In this systematic review, we examined the relationship between levels of cholesterol and markers of cholesterol turnover in circulation and/or cerebrospinal fluid (CSF) and disease outcomes in adults with clinically isolated syndrome (CIS) or confirmed MS. Studies suggest that elevated levels of circulating low density lipoprotein cholesterol (LDL), total cholesterol, and particularly, apolipoprotein B and oxidized LDL are associated with adverse clinical and MRI outcomes in MS. These relationships were observed as early as CIS. The studies also suggest that oxysterols, cholesterol precursors, and apolipoprotein E may be markers of specific disease processes in MS, but more research is required to elucidate these processes and relationships. Taken together, the data indicate that cholesterol and markers of cholesterol turnover have potential to be used clinically as biomarkers of disease activity and may even be implicated in the pathogenesis of MS.