The majority of multiple sclerosis lesions fail to remyelinate after chronic demyelinating episodes resulting in neurologic disability. In the current study, chronic demyelination was investigated by using the cuprizone model, a toxic demyelination model. C57BL/6 mice were administered a 0.2% cuprizone diet up to 16 weeks to induce chronic demyelination. For comparison, another group was maintained only for 6 weeks on cuprizone to model acute demyelination. Both groups were analysed regarding the remyelination process after withdrawal of the toxin. Reexpression of myelin proteins after chronic demyelination was reduced by a factor of two as judged by LFB and myelin protein stainings compared to acute demyelination after 2 weeks on remyelination. During chronic demyelination mature oligodendrocytes (Nogo-A positive cells) were severely depleted by 90% compared to age matched controls. Nevertheless, extensive remyelination occurred after withdrawal of cuprizone and was nearly complete after 12 weeks. There was only minimal acute axonal damage as judged by APP staining, with the course of APP positive axons correlating with macrophage/microglia accumulation. Chronic axonal damage detected by SMI-32 positive staining was only seen after chronic demyelination and was still observable during the whole remyelination period. These data suggest that two pattern of axonal injury occur in the cuprizone model.