A transgenic mouse model was used to address an unsolved question in the pathogenesis of poliomyelitis: how poliovirus invades the central nervous system (CNS). LD50 values for intramuscular and intracerebral inoculation of poliovirus in transgenic mice expressing poliovirus receptors (TgPVR mice) were similar. After intramuscular inoculation with poliovirus, paralysis was observed first in the inoculated limb. In contrast, localization of initial paralysis to the inoculated limb was not observed in normal mice inoculated intramuscularly with the mouse-adapted P2/Lansing poliovirus strain. After intramuscular inoculation, infectious poliovirus was first detected in the inferior segment of the spinal cord, then in the superior spinal cord and the brain. Sciatic nerve transection blocked poliovirus spread to the spinal cord after inoculation into the hindlimb footpad of TgPVR mice. These results demonstrate that in TgPVR mice, poliovirus spreads from muscle to the CNS through nerve pathways and that expression of the poliovirus receptor plays an important role in viral spread by this route.