The agents of prion diseases have the capacity to efficiently infect susceptible hosts by peripheral routes and to project to clinical target areas of the central nervous system (CNS) via peripheral nerves. Understanding the process of prion spread from the site of infection to the CNS may allow us to identify novel therapeutic strategies. To investigate the mechanism involved in the intranerval transit of 263K scrapie prions in golden Syrian hamsters (GSHs), we transected the sciatic nerve at increasing times post-footpad injection and recorded the incubation periods as estimates of the efficiency of infection. We calculated that intranerval transit of this strain of scrapie is at least 10 times faster than previously reported and may reach 50 mm/day, similar to other neurotropic viruses. By in vivo exposure/injection of sciatic nerves to 263K infectivity, we have also shown that prion entry likely occurs via nerve terminals rather than by direct contact with the sciatic nerve. Application of this experimental approach in other forms of prion diseases could allow verification of the timing of neuroinvasion, a relevant parameter for the definition of therapeutic interventions.