Recent evidence supports a role for metabotropic glutamate receptors (mGluRs) in neuroinflammatory diseases. In the present study, we have investigated whether the group III mGluR subtypes mGluR4 and mGluR8 are expressed in MS lesions at various stages of evolution. In control patient tissue and in normal-appearing MS white matter (NAWM), no microglial or astrocyte staining was detected. In contrast, in active lesions, mGluR8 immunoreactivity (IR) was detected in cells of the microglia/macrophage lineage. Fewer macrophage-like cells were positive for mGluR8 in chronic active and inactive lesions. No mGluR4 IR was detected in cells of the microglia/macrophage lineage in the MS lesions studied. In chronic active lesions, however, a population of reactive astrocytes localized in the rim of the lesions expressed both mGluR4 and mGluR8. Our results suggest a role for these receptor subtypes in the inflammatory response in MS that involves both astrocytes and cells of the microglia/macrophage lineage.