IN mice injected with mouse-passaged scrapie, the earliest rise in titre of agent is found in organs of the lymphoreticular system—irrespective of whether the injection is intracerebral or by a peripheral route1–4. The titre of agent in the spleen, for example, can rise fairly quickly to a moderate plateau level and subsequently starts to increase progressively in the brain, where it reaches, during the clinical phase, a greater concentration than elsewhere. These generalisations are based on work in various laboratories with agent strain–mouse strain combinations having relatively short incubation periods in the range 150–300 d after injection of high doses of agent. Evidence of replication in the spleen is therefore an indication that the animal will eventually develop scrapie if it lives long enough.