Previous studies have shown that the patterns of disease-specific prion protein (PrP(d)) accumulation in the brain (the 'PrP(d) profile') of scrapie-affected sheep are mainly influenced by the source of scrapie agent. We have now extended those studies to investigate the effect of different PrP antibodies on the PrP(d) profile of scrapie- and bovine spongiform encephalopathy (BSE)-affected sheep. Immunohistochemical examination of brains of 20 sheep was performed with four different PrP antibodies (P4, 521.7, 505.2 and R486), and the animals were allocated to four groups of five sheep each depending on the transmissible spongiform encephalopathy (TSE) agent source (two natural scrapie sources, SSBP/1 and BSE). Although the PrP(d) profiles depended on the antibody used, the four TSE sources could always be differentiated. Natural Suffolk scrapie showed the highest levels of glia-associated PrP(d), natural Welsh Mountain scrapie uniquely had consistent vascular PrP(d) plaques, SSBP/1 produced the highest intracellular accumulations of PrP(d) and BSE led to moderate accumulation of all PrP(d) patterns except for vascular plaques. The variations in PrP(d) profile between TSE sources appeared to be the result of variations in cell tropism and in PrP processing. These processing differences are possibly associated with changes in PrP(d) conformation, and are manifest as differences in intracellular truncation and in release to the extracellular space of the abnormal protein. Moreover, variations in PrP(d) conformation would appear to be also influenced by the cell type supporting infection, arguing that it is modulated by the interaction between the infectious agent and the host.