The pathogenesis of 139A scrapie has been studied in CW mice infected intraperitoneally (i.p.), intravenously (i.v.) or subcutaneously (s.c.). In mice splenectomised before i.p. infection, the evidence points to a neuroinvasive pathway from visceral lymph nodes (and other sites of scrapie replication in the peritoneum) to the thoracic spinal cord. However, in non-splenectomised mice, the major neuroinvasive pathway is clearly from spleen to thoracic cord because i.p. incubation periods are shorter and replication in the thoracic cord starts correspondingly earlier than in splenectomised mice. Studies of splenectomy at different times after i.p. infection show that pathogenesis becomes independent of the spleen once infection has initiated scrapie replication in the spinal cord. The simplest interpretation of all the evidence favours the spread of scrapie infection along splenic nerve fibres to the thoracic spinal cord. The same neuroinvasive pathway is suggested by the findings using the s.c. and i.v. routes of infection. In addition it was found that the 100-fold greater efficiency of infection by the i.v. compared to the i.p. route was entirely dependent on the spleen, because splenectomy before i.v. infection reduced its efficiency to the same as that found in i.p. infected (non-splenectomised) mice.