Abnormal forms of a host protein, PrP, accumulate in the central nervous system in scrapie-affected animals. Here, PrP protein was detected immunocytochemically in tissue sections of spleen, lymph node, Peyer's patches, thymus, and pancreas from uninfected mice and from mice infected with a range of mouse-passaged scrapie strains and bovine spongiform encephalopathy (BSE). In the spleen, lymph node and Peyer's patches, PrP-positive cells were identified as follicular dendritic cells (FDC) by their location, appearance, and immune complex trapping function, whereas in the thymus they appeared to be two types of stromal cells: interdigitating cells (IDC) and cortical epithelial cells. In pancreas, PrP-containing cells were confined to the islets of Langerhans. Although the distribution of PrP immunolabelling was the same in tissues from scrapie-affected and uninfected mice, there was evidence that PrP accumulated in abnormal forms in FDC of infected mice. If, as is likely, PrP is essential for agent replication, our results suggest that FDC are the site of scrapie and BSE replication in the spleen and lymph node.