PrPSc is believed to serve as a template for the conversion of PrPC to the abnormal isoform. This process requires contact between the two proteins and implies that there may be critical contact sites that are important for conversion. We hypothesized that antibodies binding to either PrPcor PrPSc would hinder or prevent the formation of the PrPC-PrPSc complex and thus slow down or prevent the conversion process. Two systems were used to analyze the effect of different antibodies on PrPSc formation: (i) neuroblastoma cells persistently infected with the 22L mouse-adapted scrapie stain, and (ii) protein misfolding cyclic amplification (PMCA), which uses PrPSc as a template or seed, and a series of incubations and sonications, to convert PrPC to PrPSc. The two systems yielded similar results, in most cases, and demonstrate that PrP-specific monoclonal antibodies (Mabs) vary in their ability to inhibit the PrPC-PrPSc conversion process. Based on the numerous and varied Mabs analyzed, the inhibitory effect does not appear to be epitope specific, related to PrPC conformation, or to cell membrane localization, but is influenced by the targeted PrP region (amino vs carboxy).