Prions consist of PrP (Sc), a misfolded version of the cellular protein PrP (C). They occur in a variety of strains that share the amino acid sequence of PrP but differ in phenotypic properties, such as cell tropism and pathogenicity; strain-ness is attributed to the conformation of PrP (Sc). To gain insight as to how susceptibility of cells to a given prion strain comes about, we compared amplification of RML prions by PMCA, using cell lysates from related, RML-resistant and RML-susceptible cell lines as substrate. We found that both lysates supported amplification of RML PrP (Sc) equally well, despite a 280-fold difference in the susceptibility of the cells from which they were derived. Thus, susceptibility is an attribute of the intact cell.