New evidence supports an association between the cholesterol pathway and cognitive impairment in multiple sclerosis (MS). Cholesterol pathway biomarkers in serum from people with MS and healthy individuals were analysed for interaction with measures of cognitive and physical disability. In people with MS, higher LDL and total cholesterol levels were associated with poorer performance on the Symbol Digit Modalities Test for cognitive impairment and the Nine-hole Peg Test for dexterity. By contrast, HDL cholesterol and apolipoprotein A-I seemed to have protective roles. The findings indicate that cholesterol modulation could improve cognitive outcomes in MS.