THE prion protein PrP^c is a glycoprotein of unknown function¹ normally found in neurons² and glia³. It is involved in diseases such as bovine spongiform encephalopathy (BSE), scrapie and Creutzfeldt–Jakob disease⁴. PrP^Sc, an altered isoform of PrP^c that is associated with disease, shows greater protease resistance and is part of the infectious agent, the prion^5,6. Prion diseases are characterized by neuronal degeneration, gliosis and accumulation of PrP^Sc (ref. 7). Mice devoid of PrP^c are resistant to scrapie⁸. A fragment of human PrP consisting of amino acids 106–126 that forms fibrils in vitro is toxic to cultured neurons^9–11. Here we show that this toxic effect requires the presence of microglia which respond to PrP106–126 by increasing their oxygen radical production. The combined direct and microglia-mediated effects of PrP106–126 are toxic to normal neurons but are insufficient to destroy neurons from mice not expressing PrP^c.