We hypothesized that antibodies binding to PrP c and/or PrP Sc might hinder or prevent the formation of the PrP C -PrP Sc complex and thus prevent the conversion process. We compared the effect of individual PrP-specific monoclonal antibodies (Mabs) on the PrP C -PrP Sc conversion process using both an N2a/22L cell culture model and the test-tube PMCA system. Our results demonstrate that the Mabs have a range of inhibitory effects on the PrP C -PrP Sc conversion process. The degree of inhibition is Mab specific and more dependent on the antibody targeting region than on the specific epitope being recognized. Furthermore, since the PMCA-based method is dose-dependent and rapid, it may serve as an ideal screening assay for potential inhibitors of both PrP Sc accumulation and the progression of prion diseases.