The prion protein (PrP) is a cell surface glycoprotein normally associated with neurones. Expression of the prion protein in cultured mouse myoblasts and myotubes suggests that the prion protein may play a physiological role in skeletal muscle. When myotubes differentiate from myoblasts prion protein expression is upregulated. Accompanying this increase is an upregulation of Cu/Zn superoxide dismutase (SOD-1) in myotubes. Muscle cells derived from mice deficient in cellular PrP (PrP C ) show little increase in SOD-1 after differentiation from myoblasts to myotubes. Myoblasts and myotubes are resistant to the toxicity of a neurotoxic prion protein peptide (PrP106-126). However, in the presence of murine microglia, PrP106-126 causes a reduction in cell number. This effect is greater on myotubes than myoblasts. Even in the presence of microglia PrP106-126 is not toxic to muscle cells derived from PrP-deficient mice. Our results suggest that PrPc expression is associated with regulation of cellular resistance to oxidative stress in skeletal muscle.