Progressive degeneration of outer retinal structures occurs in hamsters with scrapie. In order to determine the relationship between histopathologic changes and replication of the scrapie agent, hamsters were inoculated intracerebrally with approximately 10(7) ID50 units. Animals sacrificed at 50 days after inoculation showed no signs of neurologic dysfunction, but had high titers of the scrapie agent or prions in both neural and nonneural portions of the eye. Prion titers in retina were greater than 10(7) ID50 units/ml of 10% (w/v) homogenate and equal to those found in optic nerve and brain. No histopathologic changes were seen by light microscopy in any ocular structure. At 70 days after inoculation, neurologic dysfunction was profound. The titers of the scrapie agent in brain, lens, retinal pigment epithelium, cornea, retina, and optic nerve were not significantly changed compared to those found at 50 days; however, retinal degeneration was severe. No morphologic changes were observed in cornea, pigment epithelium or optic nerve. These findings show that scrapie prion replication to maximal levels precedes the onset of degenerative changes in retina. Furthermore, the retina is preferentially susceptible to the degeneration induced by the scrapie agent while the other ocular structures containing significant levels of prions seem to escape injury.