The immune system is central in the pathogenesis of scrapie and other transmissible spongiform encephalopathies (TSEs) or'prion'diseases 1. After infecting by peripheral (intraperitoneal or oral) routes, most TSE agents replicate in spleen and lymph nodes before neuroinvasion 2. Characterization of the cells supporting replication in these tissues is essential to understanding early pathogenesis and may indicate potential targets for therapy, for example, in'new variant'Creutzfeldt-Jakob disease. The host'prion'protein (PrP) is required for TSE agent replication 3, 4 and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on follicular dendritic cells (FDCs) in lymphoid tissues of patients with'new variant'Creutzfeldt-Jakob disease 5, sheep with natural scrapie 6 and mice experimentally infected with scrapie 7. The normal protein is present on FDCs in uninfected mice 7 and, at lower levels, on lymphocytes 8. Studies using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis 9. To clarify the separate roles of FDCs and lymphocytes, we produced chimeric mice with a mismatch in PrP status between FDCs and other cells of the immune system, by grafting bone marrow from PrP-deficient knockout mice 4 into PrP-expressing mice and vice versa. Using these chimeric models, we obtained strong evidence that FDCs themselves produce PrP and that replication of a mouse-passaged scrapie strain in spleen depends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow-derived cells.