To elucidate whether the neurotoxic effect of a prion protein fragment (PrP106-126) is in some way mediated by the cellular isoform of the prion protein (PrPC), dissociated cortical cell cultures were prepared from mice in which the PrP gene had been disrupted (PrP0/0 mice). Cell survival after 10 days in culture was tested with an MTT assay. PrP106-126 applied every second day for 10 days in cultures from normal mice resulted in the death of 34% more cells than in untreated cells. When PrP106-126 was applied to cultures from mice lacking PrPC expression, survival was equal to or greater than that of untreated control cells. These results support the notion that expression of PrPC is required for the neurotoxic effect of PrP106-126.