Exposure of susceptible neuroblastoma N2a cells to mouse scrapie prions leads to infection, as evidenced by the continued presence of the scrapie form of the prion protein (PrP^Sc) and infectivity after 300 or more cell doublings. We find that exposure to phosphatidylinositol-specific phospholipase C (PIPLC) or to the monoclonal anti-prion protein (PrP) antibody 6H4 not only prevents infection of susceptible N2a cells but also cures chronically scrapie-infected cultures, as judged by the long-term abrogation of PrP^Sc accumulation after cessation of treatment. A nonpassaged, stationary infected culture rapidly loses PrP^Sc when exposed to the antibody or PIPLC, indicating that the PrP^Sc level is determined by steady state equilibrium between formation and degradation, and that depletion of the cellular form of PrP can interrupt the propagation of PrP^Sc. These findings encourage the belief that passive immunization may provide a therapeutic approach to prion disease.