We recently demonstrated that human, but not mouse, invariant NKT cells recognize sulfatide presented by CD1d. Sulfatide derived from myelin or from human cerebrospinal fluid (CSF) apolipoprotein E (apoE) is capable of activating human iNKT cells. We considered the pathophysiologic contexts in which CSF apoE-bound sulfatide may be capable of activating iNKT cells, namely upon disruption of the blood-brain barrier (BBB). We found that serum lipoproteins are present in the brain of MS patients in active and pre-active lesions where there is BBB disruption. In vitro, while sulfatide exclusively resides in apoE fractions within CSF, it more broadly distributes in lipoprotein fractions in human serum and its ability to activate iNKT cells is enhanced. The addition of serum VLDL-apoE to CSF also enhances the antigenicity of sulfatide. The differential ability of different lipoprotein fractions in the CSF and the serum to affect sulfatide is likely to be of importance to neuroinflammatory conditions such as multiple sclerosis (MS) and traumatice brain injury (TBI).