Astrocyte-derived cholesterol supports brain cells under physiological conditions. However, in demyelinating lesions, astrocytes downregulate cholesterol synthesis and the cholesterol that is essential for remyelination has to originate from other cellular sources. Here, we show that repair following acute versus chronic demyelination involves distinct processes. In particular, we found that in chronic myelin disease, when recycling of lipids is often defective, de novo neuronal cholesterol synthesis is critical for regeneration. By gene expression profiling, genetic loss of function experiments and comprehensive phenotyping, we provide evidence that neurons increase cholesterol synthesis in chronic myelin disease models and MS patients. In mouse models, neuronal cholesterol facilitated remyelination specifically by triggering OPC proliferation. Our data contribute to the understanding of disease progression and have implications for therapeutic strategies in MS patients.