The spleen is an important early site of prion replication and neuroinvasion after peripheral infection. (A) In 1967, Eklund et al. [17] showed that high levels of RML scrapie prions accumulated in the spleens of Swiss mice within days after subcutaneous injection, and this occurred before the prions were detected in the spinal cord and brain. Heatmap shows negative log10 of dilution of tissue suspension that contained 1 LD50/30 µL when injected intracerebrally into recipient mice. (B) In 1970, Fraser and Dickinson [21] showed that splenectomy before IP injection of C57BL/Dk mice with ME7 scrapie prions significantly extended the survival times. Bars, mean ± SEM; n = 3–22 mice/group. (C) In 1989, Kimberlin and Walker [31] concluded that splenectomy did not extend survival times once infection was established in the spinal cord. In their experiment Compton White mice were IP injected with 139A scrapie prions and the splenectomy performed at the times indicated after prion injection. Bars, mean ± SEM; n = 4–9 mice/group.