INTRODUCTION: The EBI2 receptor is one of the key mediators of innate immune responses. In cooperation with its ligand, oxysterol 7α,25HC, EBI2 coordinates immune cell positioning in the secondary lymphoid tissue, enabling appropriate humoral and cellular immune responses. EBI2 is also expressed in the central nervous system (CNS), where it regulates inflammatory signalling and myelination. Importantly, EBI2 receptor’s altered expression and signalling have been linked to a range of diseases including multiple sclerosis. AIM(S): The aim of the study was to investigate the effects of EBI2 signalling on lipid parameters in the cuprizone model of demyelination. METHOD(S): 37-week-old EBI2 knock-out (KO) and wild‑type C57BL6J mice were fed a 0.2% cuprizone diet for 5 weeks. The animals were decapitated immediately after 5 weeks or after an additional 2 weeks of recovery period on normal diet. Here, we report greater loss of brain cholesterol and triglycerides in EBI2 KO mice after 5 weeks on the cuprizone diet, indicating EBI2 receptor involvement in CNS lipid maintenance under demyelinating conditions. RESULTS: However, two weeks after return to normal diet, when spontaneous remyelination is observed, the data showed higher cholesterol and triglycerides levels and a greater increase in lipase activity in the EBI2 KO mice. Other studies showed that a sharp increase in lipase activity is observed in an experimental autoimmune encephalomyelitis model around the time of symptom remission and in cerebellar slices between deand re‑myelination phases. CONCLUSIONS: Our data is, therefore, in line with these findings showing that earlier lipase activity in the EBI2 KO mice possibly leads to an earlier remyelination attempt, as observed by increased cholesterol and triglycerides levels. These results indicate functional involvement of EBI2 receptor in lipid homeostasis under pathophysiological conditions and thus warrant further investigations into the role of EBI2 in demyelinating diseases.