Prion diseases are characterized by the accumulation of PrPSc, an aberrantly folded isoform of the host protein PrPC. Specific forms of synthetic molecules known as dendrimers are able to eliminate protease resistant PrPSc in both an intracellular and in vitro setting The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrPSc in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrPSc by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups.