We investigated the role of Haptoglobin (Hpt) in modulating the activity of Lecithin-cholesterol acyl-transferase (LCAT) in cerebrospinal fluid (CSF) of patients with Multiple Sclerosis (MS). The Hpt level increases in the CSF during oxidative stress. Under this condition, Apolipoprotein A-I (ApoA-I) and Apolipoprotein E (ApoE), that play important roles in cholesterol metabolism, undergo oxidative modification. These apolipoproteins are two mayor effectors of LCAT, the enzyme producing cholesteryl esters in both plasma and CSF. Here we report that Hpt binds ApoE. Synthetic peptides used to displace Hpt from ApoE, and map the Hpt-binding site on the apolipoprotein structure. Liposomes containing 4 mM human ApoE were challenged with hydroxyl radicals in vitro, and the protein structure, as analyzed by immunoblotting, was found severely altered. Lower alteration of ApoE was found when the liposomes were oxidized in the presence of 8 mM Hpt. The CSF levels of Hpt, ApoA1 and ApoE were measured in both MS or control by Elisa and the ratio Hpt / [ApoA1+ApoE] was found positively correlated with the ratio between cholesteryl esters and unesterified cholesterol (a footprint of LCAT activity ex vivo). We suggest that Hpt influences the stimulatory function of ApoE and ApoA1 on LCAT, and protects their structure from oxidative stress in CSF.