Recent evidence supports a role for glutamate receptors in the pathophysiology of multiple sclerosis. In the present study, we have focused specifically on the expression of metabotropic glutamate receptors (mGluRs) in multiple sclerosis brain tissue. The expression of group I (mGluR1α and mGluR5) and group II (mGluR2/3) mGluRs was studied using immunohistochemistry in tissue from 12 multiple sclerosis cases and seven nonneurological controls. The expression patterns of both group I and II mGluRs in multiple sclerosis tissue differed significantly from those in control tissue. Strong mGluR1α immunoreactivity was observed in axons of the subcortical white matter, particularly in the centre of actively demyelinating lesions and in the borders of chronic active lesions. mGluR1α axonal immunopositivity was also found in normal appearing multiple sclerosis white matter, but axons in control white matter were generally negative. mGluR1α axonal labelling was associated with the presence of non-phosphorylated neurofilaments and β-amyloid precursor protein, which are sensitive markers for axonal injury and disturbed axonal transport. Changes in mGluR immunoreactivity were also observed in glia. A diffuse increase in the expression of mGluR5 and mGluR2/3 was detected in reactive astrocytes in multiple sclerosis lesions. However, only a subpopulation of reactive astroglial cells expressed mGluR1α. In addition, labelling with antibodies to mGluR2/3 and, to a lesser extent labelling with antibodies to mGluR1aα, was detected in a population of cells of the microglial/macrophage lineage that displayed a macrophage-like morphology. Our data suggest that mGluRs, like ionotropic glutamate receptors, play a role in the complex processes that are associated with the progressive brain damage in multiple sclerosis, including both glial activation and pathological changes in axons.