Abstract Systemic infection can influence the course in many diseases of the central nervous system (CNS) such as multiple sclerosis (MS), yet the relationship between infection outside the CNS and potential damage and/or protection within the CNS is still not understood. Activation of microglia is a characteristic feature of most CNS autoimmune disorders, including MS, and both protective and degenerative functions of microglia have been proposed. Hence, we analyzed the effects of a systemic inflammatory reaction induced by peripheral treatment with lipopolysaccharide (LPS) on microglial reaction and cuprizone induced de- and remyelination. We found that LPS administration delayed demyelination, which was linked with inhibition of microglial proliferation and reduced numbers of activated microglia. The phenotype of microglia changed as an increase of Toll-like receptor 4 was found. During remyelination, LPS treatment delayed the onset of myelin protein re-expression, but later there was a beneficial effect via an increase of proliferating oligodendrocyte precursor cells (OPC) and mature oligodendrocytes. Moreover, the expression of ciliary neurotrophic factor was increased in response to LPS, a growth factor known to mediate OPC proliferation. Additional experiments showed that the time window to induce LPS effects was limited and associated with the presence of microglia. In conclusion, LPS delayed demyelination and caused beneficial effects on remyelination via increasing the proliferation of OPC. These differences seem to be an effect of LPS induced microglial modulation and indicate that exposure to certain infectious agents within a given time window may be beneficial in promoting tissue repair.