In this study we evaluated stimulation of the angiotensin AT2-receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunised with myelin-oligodendrocyte-peptide (MOG) and treated for 4 weeks with C21 (0.3mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction of EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R-stimulation. C21 treated mice had a significantly better neurological score than vehicle treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R-stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and NO production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R-stimulation protects the myelin sheaths in autoimmune CNS inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.